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Sugar Sensing and Signalingin Plants: Conserved andNovel MechanismsFilip Rolland,1 Elena Baena-Gonzalez,2

and Jen Sheen2

1Department of Molecular Microbiology, Flanders Interuniversity Institute forBiotechnology (VIB10), and Laboratory of Molecular Cell Biology K.U. Leuven, 3001Heverlee-Leuven, Belgium; email: filip.rolland@bio.kuleuven.be2Department of Molecular Biology, Massachusetts General Hospital and Departmentof Genetics, Harvard Medical School, Boston, Massachusetts 02114;email: baena@molbio.mgh.harvard.edu, sheen@molbio.mgh.harvard.edu

Annu. Rev. Plant Biol.2006. 57:675–709

The Annual Review ofPlant Biology is online atplant.annualreviews.org

doi: 10.1146/annurev.arplant.57.032905.105441

Copyright c© 2006 byAnnual Reviews. All rightsreserved

1543-5008/06/0602-0675$20.00

Key Words

glucose, sucrose, trehalose, Arabidopsis, hexokinase, Snf1-relatedprotein kinase

AbstractSugars not only fuel cellular carbon and energy metabolism butalso play pivotal roles as signaling molecules. The experimentalamenability of yeast as a unicellular model system has enabled thediscovery of multiple sugar sensors and signaling pathways. In plants,different sugar signals are generated by photosynthesis and carbonmetabolism in source and sink tissues to modulate growth, devel-opment, and stress responses. Genetic analyses have revealed exten-sive interactions between sugar and plant hormone signaling, anda central role for hexokinase (HXK) as a conserved glucose sensor.Diverse sugar signals activate multiple HXK-dependent and HXK-independent pathways and use different molecular mechanisms tocontrol transcription, translation, protein stability and enzymatic ac-tivity. Important and complex roles for Snf1-related kinases (SnRKs),extracellular sugar sensors, and trehalose metabolism in plant sugarsignaling are now also emerging.

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Contents

INTRODUCTION. . . . . . . . . . . . . . . . . 676YEAST AS A MODEL SYSTEM . . . 677SUGAR SIGNALS IN PLANTS . . . 679SUGAR CONTROL OF GROWTH

AND DEVELOPMENT. . . . . . . . . 681Seed Development and

Germination . . . . . . . . . . . . . . . . . . 681Sugar and Hormone Signaling in

Early Seedling Development . . 682Vegetative and Reproductive

Development . . . . . . . . . . . . . . . . . 684Senescence and Stress . . . . . . . . . . . . 685Sugar Starvation. . . . . . . . . . . . . . . . . . 686

SUGAR SENSORS . . . . . . . . . . . . . . . . . 686The Roles of the Hexokinase

Glucose Sensor . . . . . . . . . . . . . . . . 686Cell Surface Receptors . . . . . . . . . . . . 688

MOLECULAR MECHANISMSOF SUGAR REGULATION . . . . . 689Distinct Sugar Signaling Pathways

Regulate Gene Expression . . . . . 689Transcription Control . . . . . . . . . . . . 690Genome-Wide Expression

Analyses . . . . . . . . . . . . . . . . . . . . . . 690Promoter Elements and

Transcription Factors . . . . . . . . . . 692Transcript Stability and Processing 693Translation . . . . . . . . . . . . . . . . . . . . . . 693Protein Stability . . . . . . . . . . . . . . . . . . 694

SNF1-RELATED PROTEINKINASES . . . . . . . . . . . . . . . . . . . . . . . 694A Large Superfamily of

CDPK-SnRK . . . . . . . . . . . . . . . . . 694Modulation of Enzymatic Activity

and Protein Degradation . . . . . . 695Gene Expression Regulation . . . . . 696Regulation of SnRK1 . . . . . . . . . . . . . 696

TREHALOSE . . . . . . . . . . . . . . . . . . . . . . 697CONCLUSIONS AND

PERSPECTIVES . . . . . . . . . . . . . . . . 699

INTRODUCTION

Life on earth largely depends on the pho-tosynthetic fixation of carbon and light en-ergy in energy-rich sugar molecules and theconcomitant production of oxygen. Consis-tent with their importance as the prime car-bon and energy sources for most cell types,sugars, in addition, have acquired importantregulatory functions early in evolution, con-trolling metabolism, stress resistance, growth,and development in bacteria, yeasts, plants,and animals. The regulatory roles of sug-ars (and nutrients in general) are most ex-plicit in free-living microorganisms that arechallenged by a constantly, often dramati-cally changing environment. The yeast Sac-charomyces cerevisiae (baker’s or brewer’s yeast)is a particularly well-studied eukaryotic modelsystem for sugar sensing and signaling, notin the least because of the numerous appli-cations of alcoholic fermentation. In multi-cellular organisms, maintenance of nutrientand energy homeostasis within cells and tis-sues is of vital importance and requires theconstant monitoring and adjusting of nutrientavailability. Failure to do so can have dramaticconsequences that cause life-threatening dis-eases, such as diabetes, in mammals. Inphotosynthetic, sugar-producing, and sessileorganisms like plants, maintenance of energyhomeostasis requires even more sophisticatedand flexible regulatory mechanisms to ac-count for the amazing physiological and de-velopmental plasticity seen in plants. In re-cent years, a pivotal role of sugars as signalingmolecules and their dramatic effects on plantgrowth and development have become appar-ent. Still, a great deal remains to be learnedabout the precise molecular mechanisms in-volved. There have been comprehensive re-views on various aspects of sugar regulationin plants (43, 67, 76, 111, 123). This reviewintends to provide an overview of the latestevidence supporting the central roles of sugarsignals and signaling in plant life. A com-parison of conserved and novel sugar regula-tion mechanisms in the yeast and plant model

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systems is presented. Promising future re-search directions and emerging new pathwaysand mechanisms are discussed.

YEAST AS A MODEL SYSTEM

In general, yeast has proven very useful as amodel and experimental tool for reverse ge-netics approaches of eukaryotic cell biology.Saccharomyces cerevisiae is a facultative anaer-obic organism but, even in the presence ofoxygen, prefers the fermentation of sugarslike glucose, fructose and sucrose to far moreenergy-efficient respiration. Rapid prolifera-tion and reusable ethanol production duringfermentation apparently offers a selective ad-vantage over less ethanol-tolerant microor-ganisms. This yeast therefore has developeda whole array of glucose sensing and signalingpathways to enable the optimal and exclusiveuse of this carbon source. In view of the an-cient and possibly conserved nature of cellularsugar sensing and signaling mechanisms in eu-karyotes, the pathways elucidated in yeast areintroduced concisely (Figure 1) (reviewed in112 and 113).

An important pathway, responsible fortranscriptional repression of a large numberof genes involved in respiration, gluconeoge-nesis and the uptake and metabolism of al-ternative carbon-sources, is the “main glu-cose repression pathway” (Figure 1a). Glu-cose activation of this pathway involves theglycolytic enzyme and sensor Hexokinase2(Hxk2), which interacts with the Glc7-Reg1protein phosphatase 1 (PP1) complex that de-phosphorylates and inactivates a key proteinkinase (PK), Sucrose nonfermenting1 (Snf1).In addition, Hxk2, in response to glucose,translocates to the nucleus, where it interactswith Mig1 [a zinc-finger DNA-binding tran-scription factor (TF)] to form a stable complexthat recruits co-repressor proteins (91). Basedon extensive random mutagenesis, it was con-cluded that the role of Hxk2 in glucose repres-sion was tightly associated with its catalyticactivity. However, a regulatory role for Hxk2as a glucose sensor is recently substantiated by

HXK: hexokinase

PK: protein kinase

TF: transcriptionfactor

GPCR: G-proteincoupled receptor

the isolation and characterization of new hxk2mutants with uncoupled catalytic and signal-ing activities (112, 113).

The Snf1 PK, an ortholog of mammalianAMP-activated PK (AMPK), is required forderepression of gene expression under lowglucose and starvation conditions throughphosphorylation of Mig1, which causes Mig1to dissociate from the repressor complex andsubsequently undergo nuclear export.

Due to low energy efficiency, fermenta-tive metabolism requires a high metabolic fluxthrough glycolysis. Therefore, in the pres-ence of glucose, the expression of hexosetransporters (HXTs) with appropriate affin-ity and capacity is upregulated through theaction of a second glucose signaling path-way (Figure 1b). Two catalytically inactiveHxt homologs, Snf3 and Rgt2, function ashigh- and low-affinity sensors, respectively,for extracellular glucose and activate ca-sein kinase 1 (Yck1). This HXT-inductionpathway inactivates the Rgt1 transcriptionrepressor through SCFGRR1 (ubiquitin E3ligase)- and proteasome-mediated degrada-tion of the Rgt1-interacting and -regulatingproteins Std1 and Mth1. Yck1 presumablyphosphorylates Std1 and Mth1, which aretethered from the nucleus to the C-terminaltails of the glucose sensors, thereby targetingthem for ubiquitination and degradation (61).

The third sugar-regulatory pathway in-volves cAMP-PKA signaling, which enablesthe fast growth rate on fermentable carbonsources through a phosphorylation cascade(−). Remarkably, glucose activation of cAMPsynthesis by adenylate cyclase (AC) involvesa dual mechanism. Extracellular glucose orsucrose is sensed by the G-protein coupledreceptor (GPCR) system (75), consisting ofthe Gpr1 receptor, Gpa2 (a heterotrimericGα-protein), and Rgs2, a negative regulatorof G-protein signaling. However, activationalso strictly depends on glucose uptake andphosphorylation (but no further metabolism).Some evidence again suggests a rather regu-latory role for multiple hexose kinases [Hxk1and 2 or Glucokinase1 (Glk1)], possibly

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SCFGRR1

Rgt1

YckI

Glk1

Hxk

cAMP ATP

G6P

Hxt

Tps2

T6P

Tre

Tps1

Fermentation

Nucleus

Hxk2

Snf1

Glc7

Reg1

Std1 Mth1AC

Ras

Gpa2Rgs2Hxt

Snf3

Rgt2

Gpr1

G6P

b

c

d

a

Msn2 Msn4Mig1

Yeast

Plasma membrane

PKA

Figure 1Glucose sensing and signaling pathways in yeast. (a) The main glucose repression pathway. Hexokinase 2(Hxk2) acts as a sensor and translocates to the nucleus in response to glucose. Sucrose nonfermenting 1(Snf1) is required for derepression of gene expression under starvation conditions. (b) The HXTinduction pathway. Two hexose transporter homologs, Snf3 and Rgt2, function as glucose sensors at theplasma membrane, where they activate Casein kinase I (Yck1). (c) The cAMP-dependent Protein KinaseA (PKA) pathway with a dual sensing system for glucose activation: extracellular glucose (and sucrose)sensing by the G-protein coupled receptor (GPCR) system and intracellular hexose phosphorylation. (d )Glycolytic activity and gene expression are controlled by metabolic intermediates, includingtrehalose-6-P (T6P), which inhibits Hxk2 activity. High and low levels of glucose (black dots) and sucrose(double dots) are indicated. See text for details.

through activation of the small Ras G-proteins, which are required for (basal) AC ac-tivity. In addition to stimulating glycolyticactivity and mobilization of reserve carbohy-drates and ribosomal protein gene expression,PKA activity also dramatically reduces stressresistance during growth on glucose throughinactivation (phosphorylation and cytoplas-mic translocation) of the Msn2 and Msn4TFs. These TFs, isolated as multicopy-suppressors of the snf1 mutant phenotype,

activate gene expression in the absence ofhigh glucose levels by binding to stressresponse elements (STRE) in the promotersof stress-regulated genes. PKA also integratessignaling by other essential nutrients such asphosphate, sulphate, and nitrogen sources.

Finally, metabolic intermediates are in-volved in expression and (allosteric) activityregulation of glycolytic enzymes (Figure 1d ).Unexpectedly, mutant alleles conferring ageneral glucose-sensing defect are affected in

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the trehalose-6-P (T6P) synthase gene TPS1.Trehalose has a dual function as a storage car-bohydrate and stress protectant in microor-ganisms and is accumulated mainly duringstarvation conditions. In addition, trehalosemetabolism plays a vital role in controllingyeast glycolysis, at least in part through theallosteric inhibition of T6P on HXK activity.

Numerous regulatory interactions be-tween these different pathways enableexquisite fine-tuning of the cell’s responseto glucose availability. Interestingly, Hxk2,PKA, and Snf1 signaling have also beenimplicated in yeast longevity control, andanalogous ancient pathways appear to exist inmammals and plants.

SUGAR SIGNALS IN PLANTS

Sugar regulation is necessarily far more com-plex in plants. First, multicellular organ-isms need both long-distance and tissue- oreven cell-type-specific signaling mechanismsand coordination with both developmentand physiological and environmental changes.As autotrophic, photosynthetic organisms,plants are made up of sugar exporting (source)and sugar importing (sink) tissues and organs,and sugar signals are generated from differ-ent sources at different locations (Figure 2).Sugar metabolism is a very dynamic process,and metabolic fluxes and sugar concentrationsalter dramatically both during developmentand in response to environmental signals suchas diurnal changes and biotic and abiotic stress(11, 12, 108, 124, 146 ). Integration of en-vironmental signals with metabolism is par-ticularly important for sessile organisms. Notsurprisingly, intricate regulatory interactionswith plant hormones are an essential part ofthe sugar sensing and signaling network. Fi-nally, photosynthesis and carbon metabolismand allocation are themselves subject to rig-orous feedback regulation and a prime targetof sugar signaling.

In general, source activities like photo-synthesis, nutrient mobilization, and exportare upregulated under low sugar conditions,

Figure 2Sugar signals in source and sink cells. Simplified model of the major carbonfluxes and sugar signal generation by photosynthesis, transport andhydrolysis in photosynthetic source cells during the day (a) and night (b)and in sink tissue (c). See text for details. SPS, sucrose-P synthase; SPP,sucrose-P phosphatase; AGPase, ADP-glc pyrophosphorylase; UGPase,UDP-glucose pyrophosphorylase; INV, invertase; C-INV, cytosolic INV;CW-INV, cell wall INV; V-INV, vacuolar INV; SUS, sucrose synthase

T6P: trehalose-6-P

TPS: trehalose-6-Psynthase

whereas sink activities like growth and stor-age are upregulated when carbon sources areabundantly available. Photosynthesis and sinkdemand need to be rigorously coordinated,and this coordination involves both metabolic(substrate and allosteric) regulation and spe-cific sugar-signaling mechanisms. Althoughsucrose is the major photosynthetic productand transport sugar in plants, many sugar-signaling effects on growth and metabolism

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Figure 2(Continued)

CW-INV: cell wallinvertase

AGPase: ADP-glcpyrophosphorylase

C-INV: cytosolicinvertase

SUS: sucrosesynthase

V-INV: vacuolarinvertase

G6P: glucose-6-P

can be attributed to the action of its hydrolytichexose products, glucose and fructose (or theirdownstream metabolic intermediates). How-ever, recent studies suggest that sucrose andtrehalose (or T6P) regulate specific responsesthat are not affected by hexoses (see below).

A current, simplified model of the majorcarbon fluxes in plants shows where sucroseand hexose signals can be generated and per-ceived in source and sink cells (Figure 2).In photosynthetic (source) cells (Figure 2a),photosynthate generated in the Calvin cycleis exported, mainly as triose-phosphates, fromthe chloroplast to the cytosol, where it is usedin glycolysis (and subsequently in respirationor biosynthesis) or converted to sucrose forlocal use or export to sink tissues. Net export

or import of sucrose depends on the source orsink status of the leaf cells. Biotic or abioticstress and hormonal signals can also inducecell wall invertase (CW-INV) expression andsink formation in leaf tissue (7, 109). Excessphotosynthate is transiently stored as starch inthe chloroplast during the day. ADP-glucosepyrophosphorylase (AGPase), a key enzyme instarch synthesis, is highly regulated by sugars(28, 42, 69). A major source for glucose signalsis transitory starch breakdown from chloro-plasts in leaf cells during the night (mainly viamaltose and glucose export; Figure 2b) andfrom plastids (amyloplasts) in starch-storingorgans (124, 145).

In sink tissues (Figure 2c), sucrose canbe imported into cells through plasmodes-mata (symplastic transport) or the cell wall(apoplastic transport). Intracellular sucrose iscleaved by cytoplasmic INV (C-INV), gen-erating glucose and fructose, or by sucrosesynthase (SUS) producing fructose and UDP-glucose. Sucrose can also be imported andstored in the vacuole, and vacuolar INV(V-INV) is a major intracellular source ofhexoses in expanding tissues. In the apoplast,extracellular sucrose is hydrolysed by CW-INV, a major driving force in sugar unloadingand gradient maintenance and therefore sinkstrength. These enzymes generate high lev-els of extracellular glucose and fructose thatare taken up by hexose transporters, which arecoexpressed and coordinatedly regulated withCW-INV (109).

It is clear that sucrose transport and hy-drolysis play key regulatory roles in carbonallocation and sugar signal generation. Theextensive feedback regulation of the INVs andSUS by sugar signaling generates a very sen-sitive self-regulatory system (67). The actualsituation is more complex with transport ofsugars and intermediates in and out of plas-tids (145) and vacuoles. Interestingly, sub-stantial direct glucose-6-P (G6P) to glucoseconversion by glucose-6-phosphatase activityis also observed in maize root tips (2). Be-sides photosynthesis and breakdown of su-crose and starch, the hydrolysis of cell wall

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polysaccharides also likely generates sugarsignals. Several cell wall glycosyl hydrolasesare upregulated under stress conditions suchas dark, sugar depletion, senescence and in-fection (23, 40, 74; J. Sheen, unpublished ob-servations). Sugar signaling also needs to beintegrated with the availability of other essen-tial nutrients, such as nitrogen, phosphate andsulfate. Diurnal changes in nutrient availabil-ity are anticipated by the plant, and circadianregulation of enzymes involved in carbon al-location contributes significantly to an opti-mal use of the available resources. Moreover,recent studies have offered strong evidencefor the critical role of sugar signaling in theactual regulation of diurnal gene expression(11, 33).

SUGAR CONTROL OF GROWTHAND DEVELOPMENT

Seed Development and Germination

Our understanding of sugar regulation ofgrowth and development has benefited fromstudies on (mainly legume and especiallybean) embryo and seed development. Theseprocesses are characterized by well-defineddevelopmental and metabolic transitions(146). For example, during early seed develop-ment, high maternal CW-INV activity gen-erates high hexose levels that promote em-bryo growth by cell division. High-resolutionhistographical mapping reveals a clear cor-relation between free glucose concentrations(present in spatial gradients) and mitotic ac-tivity in developing cotyledons (13). This rolefor glucose as a developmental trigger or even“morphogen” is possibly mediated by sugar(and cytokinin) control of cyclinD gene ex-pression (107). d-type cyclins are involved inthe G1/S transition, which in yeast and mam-mals is also controlled by nutrient availabil-ity. CYCD3;1 expression appears to be asso-ciated primarily with proliferating tissues anddownregulation of CYCD3;1 might be an im-portant factor in mitotic cell cycle exit and

Figure 2(Continued)

the onset of cellular expansion and differen-tiation (31). In the moss Physcomitrella patens,targeted cycD gene knockouts exhibit devel-opmental progression independent of sugarsupply but have no obvious morphologicalphenotype (83). During the so-called transi-tion phase, the embryo switches from a mainlymitotic growth to differentiation and growthdriven by cell expansion. This switch is as-sociated with a strong transient increase insucrose uptake and the establishment of em-bryo sink strength. During this phase, freehexose levels decrease dramatically and themetabolic flux is redirected to storage prod-uct accumulation (mainly starch and nitrogenin the case of pea seeds). Sucrose, in general,appears to be rather associated with the reg-ulation of storage- and differentiation-related

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ABA: ABSCISICACID(SYNTHESIS)

GIN: GLUCOSEINSENSITIVE

processes, in part through the regulation ofmetabolic enzyme gene expression and activ-ity (146). The transition phase is also markedby a shift from high maternal CW-INV activ-ity to high filial SUS activity.

Arabidopsis seed development follows asimilar format with the major difference that itstores mainly lipids. A recent microarray studyhas initiated the dissection of the contrapuntalnetworks of gene expression during seed fill-ing (115). Interestingly, the wrinkled1 mutant,that has a severely reduced seed oil content, isdeficient in a putative APETALA2 (AP2)-typeTF that controls glycolytic gene expressionand activity necessary for the conversion of su-crose into triacylglycerol biosynthesis precur-sors (16). Remarkably, loss-of-function muta-tions in the AP2 TF itself, best known for itsinvolvement in flower development, increaseseed mass and yield (60, 94). The increasedcell size and number in the mutant embryosis associated with an increased hexose to su-crose ratio throughout embryo development(94); this observation suggests that this TF ex-erts its effect by modulating sugar metabolismand thereby signaling and development. Inthe storage stage of Arabidopsis embryogene-sis, trehalose metabolism also plays an essen-tial role (35; see below).

Although supplementation of exogenoussugars relieves the inhibition of germina-tion by added ABA or mannose, glucose in-hibits Arabidopsis seed germination (30, 105).Glucose-delayed seed germination is ABA-dependent but not caused by an increase incellular ABA concentrations. This delay israther associated with a slowing down of thedecline in endogenous ABA important forthe last stage of seed maturation and dessica-tion. It appears that glucose and ABA interac-tions vary when their concentrations change.In addition, some sugar and ABA signalingmutants display normal germination kinetics(105), suggesting the involvement of specificsignaling pathways in germination and differ-ential responsiveness to sugars depending onthe developmental stage.

Sugar and Hormone Signaling inEarly Seedling Development

Positive interactions between sugar and ABAsignaling are more obvious during earlyseedling development (43, 76). ABA medi-ates a postgermination developmental arrestcheckpoint that enables the germinated em-bryos to cope with new, adverse growth con-ditions (82). During Arabidopsis early seedlingdevelopment, high levels of exogenous sug-ars similarly repress hypocotyl elongation,cotyledon greening and expansion, and shootdevelopment.

The developmental arrest phenotype hasenabled different groups using somewhatdifferent screening conditions to isolatea number of sugar-insensitive and sugar-hypersensitive mutants in Arabidopsis. Thesemutants are often allelic, and their charac-terization has revealed extensive and inti-mate connections between sugar and planthormone signaling pathways (Figure 3) (re-viewed in 43, 76, and 111). Notably, sev-eral of the sugar mutants isolated turnedout to be allelic to known ABA synthesis(aba) and ABA insensitive (abi) mutants. Acentral role for ABA in plant sugar signal-ing was substantiated by the characterizationof glucose insensitive5 (gin5) and gin6/sucroseuncoupling6 (sun6)/sugar insensitive5 (sis5) asmutant alleles of ABA3 and the gene thatencodes the AP2-type transcription factorABI4, respectively (3, 43, 76). The glucose-insensitive sis4/gin1 mutants are allelic to aba2,which is deficient in a short-chain dehydro-genase/reductase (SDR1) required for ABAsynthesis (21, 43, 76). Exogenous glucosespecifically increased both (a) expression ofABA synthesis and signaling genes and (b)endogenous ABA levels (21). This suggeststhat glucose-specific accumulation of ABA isrequired for glucose signaling during earlyseedling development. The fact that not all abimutants are glucose insensitive during earlyseedling development indicates that thereare multiple pathways for glucose and ABAsignaling (3).

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ABI8

ABI3

ABI4

ABI5

ABF2

ABF3

ABF4

ABA1

ABA2

ABA3

AA03

Glucose Metabolism-dependent

HXK1-independent

ABA

Germination / early seedling development

ETR1

EIN2

EIN3

Ethylene

CTR1

ETO1

AuxinABF3

ABF4

ABI1

ABI2

Vegetative stress response

ARFs/IAAs ARRs

HXK1

SCFEBF1/2

Cytokinin

stress

Figure 3Model of genetic interactions between sugar and hormone signaling. HXK1-mediated glucose signalingthat controls seedling development involves an increase in ABA and induces both ABA synthesis and ABAsignaling gene expression. Glucose and ethylene signaling converge on the ETHYLENEINSENSITIVE3 (EIN3) TF to differentially regulate its protein stability. Finally, HXK-signalinginteracts positively and negatively with auxin and cytokinin signaling, respectively. Hypotheticalconnections are shown (dashed lines). See References 43, 76, 111, and text for more details.

Another hormone that clearly interactswith sugar signals in controlling seedlingdevelopment is ethylene (Figure 3). Treat-ment of wild-type seedlings with the ethyleneprecursor 1-aminocyclopropane-1-carboxylicacid (ACC) copies the gin phenotype, andepistatic analysis puts GIN1/ABA2 down-stream of the ethylene receptor ETR1 (156).Whereas ethylene insensitive mutants, etr1-1and ethylene insensitive2 (ein2), exhibit glucosehypersensitivity (156), gin4 and sis1 are mu-tant alleles of CONSTITUTIVE TRIPLE RE-SPONSE1 (CTR1), a negative regulator ofethylene signaling (21, 43, 76). A molecularlink between glucose and ethylene signaling isprovided by the finding that glucose and ethy-

lene antagonistically regulate protein stabilityof the EIN3 TF (152).

Mutant screens for altered sugar respon-siveness of germination and seedling devel-opment are not saturated, and new mutantsare still being identified. The glucose hypersen-sitive1 ( ghs1) mutant contains a T-DNA in-sertion in a plastid ribosomal protein gene(93). However, because of the extensive inter-actions between sugar and other pathways, it isexpected that more components will be iden-tified in screens and studies of other responses.The bls1 mutant, for example, was isolatedin a screen for photomorphogenic mutantsand uncovers interactions between brassinos-teroid, light and sugar (bls) responses (73).

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SnRK: Snf1-relatedkinase

Still, many sugar mutants identified by otherscreens are involved in the ABA pathway. Sev-eral sugar-insensitive and salt, low tempera-ture, and osmotic stress-resistant mutants, forexample, are allelic to aba3 or abi4 (reviewedin Reference 111). In addition, ABF2, anABA response element (ABRE) binding basicleucine zipper (bZIP) TF, is an essential com-ponent of glucose signaling (65), and over-expression of ABF3 and ABF4 also increasesglucose sensitivity (64). Whereas most ABAresponse mutants have only subtle defects inthe absence of stress, the glucose-insensitiveabi8 mutant displays severely stunted growthand male sterility (14). Interestingly, the mu-tant has reduced expression of V-INV, C-INV,and SUS genes, and glucose supplementa-tion improves viability and root growth. Con-sistent with the predominant expression ofABI8 in the root elongation zone, abi8 is al-lelic with two dwarf mutants defective in rootmeristem maintenance and cell elongation(14).

Vegetative and ReproductiveDevelopment

Local sink establishment, carbon metabolismand sugar accumulation appear to play impor-tant roles in vegetative plant growth and de-velopment, presumably in part through sugarsignal generation (Figure 2). Several linesof evidence point to a crucial role for car-bon metabolism and especially the sucrose-cleaving enzymes in plant growth and de-velopment (109). A particularly remarkablefinding is the spatially regulated expressionof genes that encode carbon metabolic pro-teins like SUS, AGPase, and Snf1-related ki-nases (SnRK) in the tomato apical meristem;these genes serve as markers for early leafdevelopment (101). Transgenic expression ofthe Arabidopsis thaliana homeobox leucinezipper transcription factor ATHB13, alsorevealed a sugar-dependent control of cotyle-don and leaf shape through the specific mod-ulation of lateral expansion of epidermal cells(51). These observations support a role for

sugar metabolism and signaling in vegetativeorganogenesis. Interestingly, source strengthappears to determine the timing of fixed de-velopmental programs. Decreased photosyn-thetic rates by antisense suppression of theRUBISCO Small subunit (RBCS) in tobacco,for example, specifically delayed early shootmorphogenesis and increased the shoot/rootratio. These results suggest that plants havea source strength threshold for full, adultshoot morphogenetic growth (137). How-ever, metabolic control of cell growth also al-lows remarkable flexibility in the response tochanging growth conditions, as exemplifiedby the gravity response of maize internodalpulvinal cells. Auxin redistribution asymmet-rically increases invertase expression and ac-tivity, and this increase results in the asymmet-rical accumulation of hexoses and differentialcell elongation across the pulvinus (80). Indark-grown Arabidopsis seedlings, exogenoussucrose can induce adventitious root forma-tion (128). Many Arabidopsis sugar mutants,such as gin1, gin2 and gaolaozhuangren2 ( glz2),exhibit abnormal growth and development(20, 21, 89). Recent exciting studies have alsodemonstrated the critical role of ArabidopsisTPS1 and T6P in vegetative growth and flow-ering (6, 117, 118, 141).

In addition to vegetative development, car-bon allocation and sugar signals also con-trol reproductive development. Induction offlowering is associated with starch mobiliza-tion and a transient increase in leaf carbo-hydrate export to the shoot apical meristem,suggesting that phloem carbohydrates are acritical factor. More specifically, the C/N ra-tio of the phloem sap increased markedly andearly during induction (24). Sucrose availabil-ity on the aerial part of the plant promotesmorphogenesis and flowering of Arabidopsisin the dark, and supplementation with 1%exogenous sucrose rescues the late-floweringphenotype of several mutants (110). How-ever, higher concentrations of exogenous sug-ars delay the transition in both wild-type andlate-flowering mutants by extending the late-vegetative phase. The concomitant delay in

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activation of LEAFY suggests that sugars cancontrol the expression of floral meristem iden-tity genes (95). Interestingly, a glycosyl hydro-lase, SUS, and asparagine synthase are puta-tive direct targets for the LEAFY TF, which isessential for flower development. Expressionof a CW-INV under a meristem-specific pro-moter causes accelerated flowering and en-hanced branching of the inflorescence andseed yield, whereas the C-INV causes delayedflowering and both reduced seed yield andbranching. These results emphasize the im-portance of the exact source, nature, and lo-cation of the sugar signals (55). More evidencefor an essential role of accurate carbon al-location in reproductive development comesfrom the male-sterility phenotypes in tobaccowith tissue-specific antisense suppression of aCW-INV (48) and antisense SnRK transgenicbarley (155). The Arabidopsis sugar-insensitivemutant glz2 shows delayed flowering, aber-rant flowers and fruits, and completely sterilegynoecium (20).

Senescence and Stress

After reproduction, the final stage in plant lifeis senescence, which is a highly regulated step-wise process controlled by complex develop-mental programs and environmental signals.Leaf senescence typically coincides with a de-cline in chlorophyll content and photosyn-thetic activity. The repressive effect of sug-ars on photosynthetic gene expression andactivity and the correlation between HXKexpression and the rate of leaf senescence(29, 89, 151) are indicative of an importantrole for HXK-dependent sugar signaling inleaf senescence. Although this is consistentwith observations in other eukaryotic organ-isms, there has been some controversy aboutthe senescence-inducing effect of sugars. Thiscontroversy is mainly due to the observationthat dark-treatment of leaves, and concomi-tant chlorophyll breakdown and starvation,can induce senescence. However, dark incu-bation of whole plants delays senescence, and,although some senescence-associated genes

(SAG/SEN) are induced by dark-incubationand repressed by sugars, a recent microarrayanalysis found significant differences in geneexpression between dark/starvation-inducedand developmental senescence (15). More-over, leaf senescence is induced by high lightand long days and is associated with hexoseaccumulation (32). More research is neededto explain the apparent contradiction betweenstarvation responses and sugar accumulationduring senescence.

The exact source of the sugar accumula-tion during senescence is not clear. In castorbean leaves, sieve tube occlusions and carbo-hydrate back-up seem to precede chlorophylldegradation during natural senescence (62).This observation suggests that phloem block-age by stress-induced callose deposition is thecause there. However, senescence is generallyassociated with massive nutrient (especiallynitrogen) remobilization and export from de-teriorating leaves, implying that basic cellu-lar metabolism and phloem transport remainfunctional until the later stages of senescence.Although it is possible that a high sugar-to-nitrogen ratio is the trigger for senescenceand nitrogen remobilisation from older leaves(103, 150), analysis of Arabidopsis recombinantinbred lines shows that late-senescing linesappear to mobilize glutamine, asparagine, andsulfate more efficiently than early-senescinglines (32).

Although ABA is known to promote senes-cence, a recent study (103) suggests that ABAis not required for the sugar-dependent in-duction of leaf senescence. Cytokinins, onthe other hand, can delay plant senescence,and studies with gin2 show that sugars andcytokinins work antagonistically (89). Inter-estingly, cytokinin-induced CW-INV expres-sion is an essential downstream component ofcytokinin-mediated local delay (green islands)of leaf senescence (7).

Senescence is also associated with the ex-pression of pathogenesis-related (PR) genes.Both exogenous sugars and overexpression ofa yeast INV in the plant vacuole or cell wallcan induce PR gene expression (54, 130, 151).

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In addition to regulating carbon partitioning,plant development, and hormone responses,INVs have an important role in stress re-sponses as central signal integrators and mod-ulators (109). CW-INV is induced by bothabiotic stress and pathogen infection to lo-cally increase respiratory sink activity and canbe regarded as a PR protein. However, PK in-hibitor studies indicate that sugars and stressregulate source and sink metabolism and de-fense responses through different pathways(36, 108). The Arabidopsis hypersenescing mu-tant hys1 provides the clearest link betweensugar, senescence, and stress signaling. Thismutant is not only hypersensitive to sugar in-hibition of seedling development and gene ex-pression, but also allelic to constitutive expressorof pathogenesis-related genes5 (cpr5) (153).

Sugar Starvation

As well as being able to sense and optimally ex-ploit carbohydrate availability, plants need tobe able to cope with carbohydrate depletion.In addition to natural diurnal fluctuations,variations in other environmental conditionscan result in sugar starvation conditions. Ingeneral, plants deal with such conditions byarresting growth and by redirecting cellularactivity towards basic metabolism and respi-ration based on protein, amino acid, and lipidcatabolism rather than glycolysis. Energy-consuming biosynthetic processes, includingprotein synthesis, are switched off (11, 23,58, 154). As in yeast and animal cells, star-vation conditions also trigger proteolysis andautophagy in plants. Arabidopsis orthologs ofthe yeast AUTOPHAGY (ATG) protein sys-tem are induced by sucrose starvation andhave been shown to be essential for nutrientrecycling and senescence (23, 132).

Starvation conditions are, however, diffi-cult to manipulate experimentally in wholeplants. Cell cultures or excised roots andleaves have often been used to study star-vation effects, including derepression of α-amylase gene expression (in rice suspension-cultured cells), the coordinated induction ofthe glyoxylate cycle (malate synthase and isoc-

itrate lyase) gene expression (in cucumber cellcultures), activation of a β-methylcrotonyl-coenzyme A carboxylase (MCCase) sub-unit gene (in sycamore cell suspensioncultures), increased mitochondrial fatty acidβ-oxidation, and increased proteolysis and ni-trogen distribution (in excised maize root tips)(reviewed in Reference 154). Interestingly, in-duction of a number of DARK INDUCED(DIN) genes in detached leaves is inhib-ited by sucrose supplementation. This indi-cates that sugar deprivation is the key factorin the induction of these genes. Consistentwith this hypothesis, DIN gene expressionis induced by addition of a photosynthesisinhibitor and in sucrose-depleted Arabidop-sis cell culture and tobacco BY-2 cells (40).Most DIN genes encode proteins involved inamino acid and carbohydrate catabolism, andsome are associated with leaf senescence (40).DIN6/ASPARAGINE SYNTHASE1 (ASN1),which encodes a glutamine-dependent as-paragine synthase, appears to be a particu-larly good reporter gene for sugar starvationconditions (11, 23, 71, 104, 134). In Ara-bidopsis culture cells, sucrose deprivation leadsto structural changes in mitochondria, a de-crease in mitochondrial volume, a reductionin the rate of cellular respiration, and globalgene expression changes (23, 45). Recent de-tailed analysis of the molecular events of dark-induced leaf senescence also revealed a promi-nent increase in asparagine levels and ASN1gene expression, and mitochodrial amino acidcatabolism (58, 78). The clever use of anArabidopsis starchless phosphoglucomutase (pgm)mutant with larger diurnal changes of endoge-nous sugar levels has facilitated the identifica-tion of genes controlled by low sugar condi-tions and the circadian clock in whole plants(11, 131).

SUGAR SENSORS

The Roles of the HexokinaseGlucose Sensor

Recent isolation and characterization ofthe Arabidopsis gin2 mutants clearly identify

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hexokinase (AtHXK1) as a core componentin plant sugar sensing and signaling (89, 152).Initial evidence for a function of plant HXKas a glucose sensor came from studies withdifferent sugars, sugar analogs, and metabolicintermediates in a mesophyll-protoplast tran-sient expression system and phenotypic anal-yses of transgenic Arabidopsis (59). HXK ge-netically functions upstream of GIN1/ABA2in the glucose-signaling pathway (156). In or-der to study the function of AtHXK1 in a morephysiological context, plants were grown un-der various light intensities that altered en-dogenous sugar levels and signals. Whereasincreased energy supply under high light ac-celerated wild-type plant growth, gin2/hxk1mutant plants remained small with reducedcell expansion. In addition to modulating de-velopmental arrest in the presence of highexogenous glucose, AtHXK1 has an impor-tant role in growth promotion as well. Anal-yses of a possible link with growth hormonesrevealed that gin2 mutant hypocotyl explantsare relatively insensitive to auxin-induction ofcell proliferation and root formation, but hy-persensitive to shoot induction by cytokinin.Consistent with this observation, seedlingdevelopment of the auxin-resistant mutantsauxin resistant1 (axr1), axr2, and transportinhibitor response1 (tir1), and plants with a con-stitutive cytokinin response or supplementedwith exogenous cytokinin is insensitive to highglucose levels (Figure 3). The gin2 mutantplants also display a clear delayed-senescencephenotype and reduced fertility. These ef-fects parallel the effects of calorie restrictionand mutations in signaling components onlongevity in other eukaryotes (89).

Most interestingly, the gin2 mutants stillhave 50% of the wild-type glucose kinaseactivity and accumulate normal sugar phos-phate levels. Moreover, there is no clearcorrelation between glucose kinase activityand glucose reduction of chlorophyll con-tent and photosynthetic gene expression. Un-coupling of metabolic and signaling activityis confirmed by the construction and analy-sis of two catalytically inactive AtHXK1 alle-

HKL:hexokinase-likeprotein

Metabolon: anenzyme complexenabling transfer ofbiosyntheticintermediatesbetween catalyticsites withoutdiffusion, therebymaximizingmetabolic flux andavoiding interference

les. Although deficient in ATP binding andphosphoryl transfer, respectively, these alle-les sustain wild-type growth, repression ofphotosynthetic gene expression, and auxinand cytokinin responsiveness when expressedin a gin2 background (89). Future func-tional characterization of the high-molecular-weight protein complexes that harbor theAtHXK1 protein will shed light on the molec-ular details of its regulatory interactions (Y.Cho & J. Sheen, unpublished observations).

The glucose kinase activity still presentin the gin2 mutants is probably not solelydue to the presence of AtHXK2. Arabidopsisencodes four more hexokinase-like (AtHKL)proteins, one of which has detectable ki-nase activity (therefore dubbed AtHXK3)(B. Moore & J. Sheen, unpublished obser-vations). HXK and HXL protein localiza-tion is expected to play an important rolein their functions (Figure 4a). A completelyfunctional glycolytic metabolon is found onthe outside of the Arabidopsis mitochondrialmembrane (44). This enables both optimalsubstrate availability and coordination of glu-cose metabolism with cellular energy de-mand. AtHXK1 protein indeed appears to bepredominantly associated with mitochondria(B. Moore & J. Sheen, unpublished observa-tions). A regulatory role for HXK in metaboliccontrol of cell death similar to the situationin mammals is therefore also possible. HXKactivities have also been detected in the cy-tosol and associated with plastids (148). Con-sistent with the fact that photosynthetic cellsgenerate glucose mainly from starch break-down, the major glucose-phosphorylating en-zyme in the moss Physcomytrella patens is anovel type of chloroplast stromal kinase (96).Such an inner-plastidic HXK has also re-cently been identified in tobacco (46). Plantsin general appear to contain two types ofHXKs: type A kinases (such as PpHxk1 andtwo Arabidopsis HKLs), which have a pre-dicted chloroplast transit peptide, and typeB kinases (such as AtHXK1 and AtHXK2),which have a membrane anchor (96; B. Moore& J. Sheen, unpublished observations).

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SnRK1

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Figure 4Model of sugar-sensing mechanisms in plants. (a) The HXK1 glucose sensor is mainly associated withmitochondria, possibly as part of a glycolytic metabolon. In addition, HXK1 is found inhigh-molecular-weight complexes in the nucleus where it controls transcription andproteasome-mediated degradation of the EIN3 TF. Other HXK and HKL proteins are also associatedwith the outer membrane of plastids, including chloroplasts, or cytosol. HXK can also be found in thechloroplast stroma. (b) Sucrose (and other disaccharides) appears to be sensed at the plasma membrane,possibly by transporter homologs. Monosaccharide transporters might have similar functions asmembrane sensors. (c) G-protein coupled receptor signaling by RGS1 and GPA1 is involved in glucosecontrol of seed germination and seedling development, possibly in a hexokinase-independent way. (d )SnRK1 proteins play an important role in plant sugar and starvation signaling, although the significanceof the regulation of these proteins by sucrose (Suc) and G6P is still unclear. (e) Important regulatoryeffects are reported for trehalose (Tre) and T6P, apparently downstream of SnRK1. In the nucleus,several types of transcription factors are involved in sugar-regulated transcription. See text for moredetails.

Surprisingly, AtHXK1 can translocate to thenucleus as well (Figure 4a) (152). More com-plex functions of HXK are anticipated in rice,in which ten functional HXK homologs havebeen identified ( J.S. Jeon, personal commu-nication). In addition to HXKs, plants alsocontain several fructokinases, some of whichmight also be involved in sugar sensing (98).Surprisingly, the gin2 mutants are insensitiveto glucose but still sensitive to fructose and

sucrose (W. Cheng & J. Sheen, unpublishedobservations).

Cell Surface Receptors

In yeast, extracellular glucose and sucrose aredetected by the Gpr1-Gpa2 system, one ofonly two GPCR systems, the other one be-ing involved in pheromone detection. An-imals use different GPCR combinations to

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function as sweet taste receptors. Remark-ably, proteins of the Type 1 Receptor (T1R)family are also expressed in the intestinaltract and enteroendocrine cells (34), wherethey could be involved in sugar sensing. Instriking contrast to animals, where GPCRsconstitute one of the major mechanisms forextracellular signal detection, plants appar-ently contain only one canonical G-proteinα-subunit (encoded by GPA1 and RGA1 inArabidopsis and rice, respectively). These pro-teins and the associated β and γ subunits havebeen implicated in a wide variety of develop-mental, light, phospholipid, and hormone re-sponses (100), oxidative stress response, andfungal disease resistance. As the yeast pro-teins are involved in sensing the most vi-tal signals (sugar and sex), one is intuitivelytempted to speculate about the involvementof hetero-trimeric G-proteins in plant sugarsensing (Figure 4b). Interestingly, GPA1 in-teracts with two putative receptor proteins: G-protein coupled receptor1 (GCR1), a seven-transmembrane domain protein with somehomology to classical GPCRS, and Regulatorof G-protein signaling1 (RGS1), an unusualhybrid seven-transmembrane domain pro-tein with a C-terminal RGS-box (19). RGSproteins typically negatively regulate het-erotrimeric G-proteins by accelerating theirintrinsic GTPase-activity. Consistent withsuch a function, loss of RGS1 increases GPA1activity, which results in increased cell elonga-tion in hypocotyls in darkness and increasedcell production in roots grown in light (19).The rgs1 mutant seedlings display insensitiv-ity to 6% glucose, whereas RGS1 overexpres-sors are hypersensitive (18, 19). Based on theuse of different sugars and sugar-analogs, it issuggested that AtRGS1 functions in an HXK-independent glucose signaling pathway (18).The gpa1 mutants are hypersensitive to ABAand sugar inhibition of germination (139).Glucose addition also causes a rapid transientincrease in the interaction of AtRGS1 withAtGPA1 at the plasma membrane and its sub-sequent internalization, possibly as a desensi-tization mechanism (P. Taylor & A. Jones, per-

sonal communication). It will be interesting toidentify the targets and processes downstreamof RGS1 and GPA1.

Another potential extracellular glucose orsucrose detection system in plants may in-volve proteins analogous to the yeast glu-cose transporter-like sensors, Snf3 and Rgt2(Figure 4c) (70). More specifically, the Ara-bidopsis and tomato SUT2 sucrose transporterhomologs, which do not have detectabletransport activity, are characterized by a longcentral cytoplasmic loop reminiscent of theSnf3/Rgt2 structure. This observation sug-gests that these proteins may have a role insucrose sensing (8). However, conclusive evi-dence for a membrane sugar sensor probablyrequires extensive mutant analysis. The use ofnonmetabolizable disaccharides has provideduseful information. For example, structure-function analysis indicates that the fructosemoiety is needed for sensing nonmetabo-lized lactulose, palatinose, and turanose disac-charide and α−amylase repression in barleyembryos (84). In addition, monosaccharidetransporters with extended cytoplasmic loopsare encoded in the Arabidopsis genome, andthe monosaccharide sugar transporter STP13acts as a heterologous multicopy suppressorof the yeast snf4� mutant growth phenotype(66).

MOLECULAR MECHANISMSOF SUGAR REGULATION

Distinct Sugar Signaling PathwaysRegulate Gene Expression

Based on the role of HXK1, three distinct glu-cose signal transduction pathways are definedin plants (151). In the first HXK1-dependentpathway, gene expression is correlated withthe HXK1-mediated signaling function. Amajor effect of this pathway is the repressionof photosynthetic gene expression. Targetgenes in this pathway can now be defined ge-netically by the gin2 mutants and catalyticallyinactive alleles (89, 151; E. Baena-Gonzalez& F. Rolland, unpublished results). A second

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pathway is glycolysis-dependent and can alsobe sustained by heterologous yeast Hxk2 ac-tivity. An example is the glucose induction ofPR1 and PR5 gene expression (151). Finally,there is evidence for HXK1-independent sig-naling pathways. Glucose induction of CHS,PAL1 and genes encoding AGPase as well asglucose repression of ASN1 are observed in-dependent of sense and antisense overexpres-sion of Arabidopsis HXK1 or overexpression ofyeast Hxk2 (151). Transcriptional responsesto nonphosphorylated glucose analogs havebeen observed in Chenopodium cell suspensioncultures, Chlorella, and transgenic Arabidopsis,although one should be cautious about pos-sible nonspecific effects of such chemicals.The glucose analog 3-OMG, not perceivedas a sugar signal, is still phosphorylated byHXK with low catalytic efficiency, and theproduct, 3-OMG-6-phosphate, accumulatesin these cells (25). Conversely, none of the 200glucose-responsive Arabidopsis genes identi-fied in a recent study responds to 3-OMG or6DOG (142).

There are a number of selected genes [e.g.,a gene that encodes a sugar beet proton-sucrose symporter (141a)], whose expressionis regulated by sucrose but not glucose orfructose; this observation points to an HXK-independent, sucrose-specific signaling path-way. Interestingly, nonmetabolizable sucrose-analogs such as palatinose and turanose canalso affect carbohydrate metabolism and geneexpression. This observation suggests the ex-istence of a di-saccharide sensing system atthe plasma membrane (Figure 4) (5, 38, 84,135). However, such analogs again have nophysiological relevance and can elicit distinctresponses consistent with their perception asstress-related stimuli.

Transcription Control

Over the years, a large number of plant geneshave been found to be transcriptionally reg-ulated by sugars, consistent with the coor-dinated regulation of source and sink activ-ities. Importantly, several genes that encode

metabolic proteins involved in sugar signalgeneration undergo transcriptional feedback-regulation by their own products. Repressionof photosynthesis gene promoters, for exam-ple, has been studied in mesophyll protoplastsand transgenic seedlings. As well as photo-synthesis genes, the INV and SUS genes arealso extensively regulated by sugar availabil-ity (67). Also, when sugar levels are high, car-bohydrate storage through starch synthesis isupregulated by the induction of genes that en-code AGPase (28).

Many sugar-regulated genes and promot-ers have been used to screen for Arabidopsismutants with potential defects in transcriptioncontrol (reviewed in References 43 and 111).A screen using the regulatory sequences of thesugar-inducible AGPase large subunit (APL3)gene fused to a negative selection marker hasidentified several impaired sucrose induction (isi )mutants. Another screen based on the activ-ity of a luciferase (LUC) reporter gene un-der the control of the APL3 promoter yieldedhigh sugar-response (hsr) mutants that exhib-ited elevated LUC activity and APL3 expres-sion in response to low sugar concentrations.The screen using sugar-regulated expressionof an Arabidopsis β-amylase generated low betaamylase (lba) and high beta amylase (hba) mu-tants with altered sugar-regulation of a sub-set of genes. Arabidopsis reduced sugar response(rsr) mutants were selected using the sucrose-activated promoter of patatin, a potato tuberstorage protein. Molecular analysis of the mu-tants will bring new information on the mech-anisms underlying sugar-mediated transcrip-tion control.

Genome-Wide Expression Analyses

From the examples described above, it is clearthat our knowledge about sugar-regulatedgene expression largely comes from data froma variety of species, mutants, tissues, develop-mental stages, and treatments. The new mi-croarray technologies now enablE genome-wide expression analyses of Arabidopsis sugarand starvation responses. Soil-grown adult

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Arabidopsis phosphorus-deficient3 (pho3) mutantplants are used specifically to study the ge-nomic response to sugar accumulation (79).This mutant is affected in the SUCROSETRANSPORTER2 (SUC2), and thereforeaccumulates soluble sugars, starch, and antho-cyanins. High expression levels of genes thatencode sucrose phosphate synthases (SPS),the plastid glucose G6P/phosphate translo-cator (characteristically expressed only inheterotrophic tissues), and the AGPase largesubunits are consistent with the starch accu-mulation in the mutant. Also consistent withthe phenotype, there is a large increase inthe expression of TFs and enzymes involvedin anthocyanin biosynthesis. Apparently, sec-ondary metabolism is also an important targetfor transcription regulation by sugars. Usinga more comprehensive approach, the short-term effects of glucose and nitrogen in globalgene expression in the dark have been studiedin liquid-grown Arabidopsis seedlings (104).The use of the protein synthesis inhibitor cy-cloheximide shows that glucose repression isa more direct process than glucose induction,which often requires de novo protein synthe-sis. TFs with sugar-regulated expression pro-files are likely regulators of the broad tran-scriptional response to sugars.

Several global gene expression studies havebeen published on sugar starvation responses.Using cDNA macroarrays and seedlingsgrown in the presence or absence of sucrose,a small number of (mostly carbohydrate andamino acid metabolism) genes were shownto be upregulated in concert during sugardepletion (74). A more detailed analysis ofnutrient mobilization in response to sucrosestarvation in Arabidopsis cells cultured in sus-pension has been carried out using the ATH1GeneChip (23). Consistent with extensive nu-trient recycling for cell survival, genes thatwere upregulated are involved in carbohy-drate, amino acid, protein and lipid catabolismand autophagy. Although these cultures werenonphotosynthetic, several photosynthesis-associated genes were also upregulated uponstarvation. Genes that were downregulated

are involved in metabolism (biosynthesis),protein synthesis, and cell division. Similarexpression profiles were observed in the re-sponses of Arabidopsis rosettes to an extendednight period and a starchless pgm mutant atthe end of the night (11, 131). These stud-ies also introduce the use of MAPMAN, apractical and informative tool to display com-plex genomic data in diagrams of metabolicand regulatory pathways. Interestingly, themolecular events in dark-induced senescenceof Arabidopsis leaves (analyzed using a combi-nation of cDNA microarray and biochemicalanalyses) exhibited extensive similarities withthe sugar starvation response. Many TF geneswere identified as putative regulators (78).However, a comparative microarray studyreveals significant differences in gene expres-sion and signaling pathways between devel-opmental and dark/starvation-induced senes-cence (15).

Extended dark treatment causes a star-vation condition that overrides the tran-scriptional regulation by circadian rhythm.However, in addition to energizing sugar pro-duction and (re)setting the clock, light canalso directly affect gene expression throughlight-specific mechanisms. In a recent study,the effects of both light and sugar were exam-ined. The results reveal that the majority of af-fected genes are co-regulated by both stimuli(133, 134). More extensive time-course geneexpression analyses using wild-type and thepgm mutant plants under a 12 h photoperiodprovide a clear picture of the essential roles ofsugar signals for a large set of circadian regu-lated genes (11).

Coordination between sugar and other nu-trient metabolic pathways is essential to op-timize the use of energy resources. A num-ber of genes involved in N-assimilation areco-regulated by sugars, and N-availabilityextensively regulates carbon-metabolic-geneexpression (26, 116, 144). Sugar responsesin general depend significantly on the N-status of the plant. Sugar repression of pho-tosynthetic gene expression, chlorophyll ac-cumulation and seedling development are

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antagonized by nitrate (89). Complex inter-actions are observed between C and N sig-naling (116, 144). The effects of nitrogen anda combination of both glucose and nitrogenhave been recently analyzed (104). Interest-ingly, most of the nitrogen responses seemto require the presence of a carbon source.A combination of microarray and extensiveinformatics analyses, classification, and mod-eling provides evidence for combined carbonand nitrogen signaling, especially in the con-trol of metabolism and energy and proteinsynthesis, even suggesting the existence of asingle CN-responsive regulatory cis-elementfor a subset of genes (97).

Oxygen availability also affects sugar sig-naling, especially the regulation of sucrosemetabolism (68). A recent microarray anal-ysis provides more insights into the effectsof sucrose on gene expression in Arabidopsisseedlings under anoxia conditions (85).

Promoter Elements andTranscription Factors

The large genomic datasets generated in mi-croarray experiments provide an excellentopportunity to identify conserved DNA el-ements in the promoters of co-regulatedgenes. Currently, most information on reg-ulatory cis-elements involved in sugar sig-naling comes from a few selected genes, en-coding sweet potato tuber and cereal seedproteins, and proteins involved in maizephotosynthesis.

Studies on sugar activation of sweetpotato tuber class I patatin, SUS, sporaminand β-amylase promoters identified severalsucrose-responsive cis-elements, includingthe Sucrose-responsive element (SURE), A-and B-boxes, the TGGACGG element, anSP8 motif, and an SP8-binding protein,SPF1 (reviewed in Reference 111). SPF1is a WRKY -type sucrose-repressed neg-ative regulator with putative orthologs inother species, including Arabidopsis. Thesefactors typically bind to (T)TGAC(C/T) W-boxes, also found in defense-related gene pro-

moters. A sugar-induced WRKY-type TF,SUSIBA2 that is expressed in barley en-dosperm binds to the SURE and W-box, butnot the SP8a element, to activate the bar-ley isoamylase1 (iso1) promoter (127). In ad-dition, a novel DNA-binding protein, des-ignated STOREKEEPER (STK), specificallyrecognizes the B-box motif to control sucrose-induced patatin expression in potato tubers(157). A more recent dissection analysis ofthe sugar/ABA-induced sweet potato spo-ramin A promoter in transgenic tobacco hasyielded a minimal promoter (Spomin) that con-tains negatively acting regions and two car-bohydrate metabolite signal responsive ele-ments (CMSRE), CMSRE-1 (TGGACGG)and CMSRE-2, in addition to the SP8a motif(92).

The most recent and fruitful studies oftransciption control have been obtained byanalyzing the sugar-inducible promoter ofa sporamin gene that encodes the mostabundant protein in sweet potato storageroots. Two putative TFs, WRI1 (activator ofSpomin::LUC1; ASML1) and a novel CCT-domain protein (ASML2) were isolated re-cently by enhancer activation-tagging of anArabidopsis line carrying the LUC reporter un-der control of a short, minimal sugar/ABA-inducible sporamin promoter. Several sugar-regulated genes, including βAMY and, in thecase of ASML2, APL3, are activated in thetransgenic lines (87, 88). Both TF genes arealso specifically induced by high sugar con-centrations. Apparently, the WRI1 TF playsan important role in directing the carbon flowtowards storage when sugar levels are high.The hsi2 mutant displays high Spomin::LUC1reporter activity even in noninducing condi-tions and is deficient in a novel B3 domaintranscriptional repressor (138).

Sugars also modulate hormone signaling atthe transcriptional level. Most obviously, glu-cose induces ABA and ABI gene expressionas a core mechanism of its signal transduc-tion (4, 21). A detailed analysis of three fac-tors involved in sugar signaling, ABI4, ABI5,and CTR1, documents their specific and

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differential regulation by glucose, ABA, stress,and developmental stage (4). Glucose repres-sion of several ethylene biosynthesis and sig-nal transduction genes suggests that interac-tions between sugar and ethylene signalingtake place in part at the transcriptional level(104). Transcriptional regulation of other hor-mone signaling components by sugars is alsolikely.

Studies with several maize photosyntheticgene promoters (119, 120) suggest the in-volvement of different regulatory elementsin sugar repression and negative control ofpositive cis-elements. Extensive studies ofsugar repression and starvation inductionof transcription have also been carried outon the promoters of rice genes that en-code α-amylases (αAMY), involved in seedstarch degradation. In a study with a minimalαAMY3 promoter, a sugar response sequence(SRS) was identified with three essential ele-ments for high sugar starvation-induced ex-pression: the GC-box, the G-box, and theTATCCA element. Interestingly, three novelMYB proteins with a single DNA-binding do-main (OsMYBS1-3) specifically bind to theTATCCA element to regulate αAMY expres-sion (86).

The identification of G-box cis-elementsprovides a link between nutrient stress andother environmental stress responses. The G-box motif (CACGTG) is, for example, in-volved in phytochrome-mediated light con-trol of gene expression and is very similar toABRE (CCACGTGG). The ABRE-bindingfactors ABF2, ABF3 and ABF4 have also beenimplicated in sugar signaling (64, 65). Anal-ysis of a conserved minimal light-responsivemodule (CMA5) recently revealed an ABI4-dependent sugar and ABA repression mech-anism involving a novel element conservedin several RBCS promoters (1). This S-boxelement (CACCTCCA) is an ABI4-bindingsite and is typically closely associated with theG-box in light-regulated promoters. Novelbioinformatics and experimental approacheswill be required to use fully the large numberof publicly available microarray data to un-

cover new regulatory elements and TF func-tions in sugar regulation.

Transcript Stability and Processing

The abundance of mRNA is not only the re-sult of transcription control. Several impor-tant regulatory effects of sugars appear to op-erate at the post-transcriptional level. Sugarrepression of rice αAMY3 involves control ofboth transcription and mRNA stability. Spe-cific sequences in the 3′ untranslated region(UTR) of the transcript can control sugar-dependent mRNA stability (17). Using thetranscription blocker actinomycin D to studymRNA half-life, several other growth- andstress-related genes have been shown to becontrolled by sugars at the level of mRNA sta-bility (56). Expression of the maize CW-INVgene Incw1 is also differentially regulated bysugars in a complex manner. In a maize cellsuspension culture, both metabolizable andnonmetabolizable sugars induce Incw1 expres-sion. However, only the sucrose- or glucose-induced increase in steady state abundance ofa smaller transcript (divergent in the 3′UTR)results in increased protein expression and en-zyme activity (22). Although the exact mech-anisms are not clear, the 3′UTR of the Incw1gene can be considered a sensor for sugar star-vation that links sink metabolism to cellularmRNA processing and translation (22).

Translation

Another level of expression regulation con-trolled by stress and nutrient starvation condi-tions is selective mRNA translation. One suchmechanism involves the presence of micro-open reading frames (μORFs) in the 5′UTR;these μORFs positively or negatively affectthe translation efficiency of the downstreamcoding sequence (CDS)/ORF. For example,transcription of the Arabidopsis S-class bZIPTF ATB2/bZIP11 is stimulated by light andsugars, but its subsequent translation is re-pressed by higher levels of sucrose. Inter-estingly, specific sucrose-induced repression

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of translation (SIRT) is dependent on theunusually long 5′UTR of the ATB2/bZIP11transcript (114). Detailed analysis has nowidentified four μORFs in the 5′UTR, oneof which (μORF2) is necessary and sufficientfor translational regulation (147). Consistentwith the differential expression regulation ofATB2/bZIP11 by sugars and its specific ex-pression pattern in vascular tissues of fertilizedovules (funiculi), seedlings, and young vascu-lar tissues, a regulatory role for ATB2/bZIP11in resource allocation to newly establishedsinks has been proposed (114). The sucrosecontrol μORF (SC-μORF) is also conservedin four other Arabidopsis and several more (of-ten stress- and hormone-induced) mono- anddicot S-class bZIP TF UTRs. In at least oneother case (AtbZIP2) the SC-μORF is essen-tial for SIRT. This suggests that the use ofμORFs is a general regulatory feature for asubset of plant bZIP TFs (147). The molec-ular details of this type of regulation and itsexact physiological importance, however, arestill unclear.

Protein Stability

Once a protein is synthesized, its activitycan still be regulated in many ways. Re-cent bioinformatic analyses suggest that over5% of the Arabidopsis proteome may beinvolved in ubiquitin-and 26S proteasome-dependent protein degradation. Consistently,protein stability and selective proteolysis haveemerged as major regulatory mechanismsin plant signaling and development, rivalingtranscription control and protein phosphory-lation (122). It is not surprising that sugarsignaling pathways also make use of thesemechanisms. Consistent with the glucoseoversensitive ( glo) phenotype for the ethy-lene insensitive (etr1, ein2 and ein3) mutantsand the gin phenotype for constitutive ethy-lene signaling (ctr1/gin4) mutants (Figure 3),glucose antagonizes ethylene signaling by en-hancing proteasome-dependent degradationof the key downstream transcriptional regu-lator EIN3 in the nucleus (152). Ethylene onthe other hand, enhances EIN3 stability (152,

41). Interestingly, the glucose response is de-pendent on AtHXK1, which can also be foundin the nucleus. Interactions with auxin andeven cytokinin signaling could involve simi-lar mechanisms. Two specific EIN3-bindingF-box proteins, EBF1 and EBF2, that formSCF complexes to repress ethylene action andpromote growth by directing EIN3 degra-dation, have been identified (41). The pre-cise molecular link of these proteins with thesugar signaling pathway remains to be eluci-dated. Interestingly, EBF1 and EBF2 are mostrelated to the yeast F-box protein Glucoserepression resistant1 (Grr1), which has beenimplicated in controlling and possibly cou-pling sugar sensing and the cell cycle. Manykey components in light, biotic and abioticstress, and hormone responses, as well as de-velopmental programs (such as flowering andsenescence) and cell cycle control are indeedwell-known targets for controlled proteolysisin plants (122). As in other eukaryotes, thehalf-life of many plant cyclin-dependent ki-nase (CDK) modulators is regulated by theproteasome (122). Interestingly, the d-typecyclin CYCD3;1, which is transcriptionallyupregulated by sucrose or glucose and cy-tokinins to enable the G1/S transition (107),appears to be a highly unstable protein and isdegraded by a proteasome-dependent mecha-nism upon sucrose depletion (102). Moreover,CYCD3;1 is phosphorylated in sugar starva-tion conditions, and a hyperphosphorylatedform accumulates in the presence of a pro-teasome inhibitor. These observations suggestthat phosphorylation is involved in targetingCYCD3;1 for destruction (102). Changes inthe expression and the enzymatic propertiesof the 20S proteasome mediated by oxidationhave been observed in sugar-starved maizeroots (9).

SNF1-RELATED PROTEINKINASES

A Large Superfamily of CDPK-SnRK

Protein phosphorylation and dephosphory-lation are key regulatory mechanisms in

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controlling protein function and activity. Ex-periments with specific inhibitors indicate theinvolvement of a variety of different PKs andprotein phosphatases (PPs) in plant sugar sig-naling. Higher plants encode a particularlylarge superfamily of calcium-dependent PKs(CDPKs) and SnRKs. Several CDPKs arespecifically induced by sucrose, and both phar-macological studies and observations of sugar-induced Ca2+-fluxes have suggested the in-volvement of Ca2+ as a second messenger insugar signaling.

The SnRK family consists of three sub-groups, based on sequence similarity anddomain structure. The SnRK1 proteins aremost closely related to yeast Snf1 and mam-malian AMPK (50). There are three membersin Arabidopsis, only two of which, AKIN10and AKIN11, are expressed (10; F. Rolland& E. Baena-Gonzalez, unpublished observa-tions). The SnRK2 and SnRK3 (also termedCBL-interacting PK or CIPK) groups areprobably unique to plants (50). SnRK1 ho-mologs from various plant species can com-plement the yeast snf1� mutant phenotype,suggesting an evolutionary conservation infunction. However, the best defined SnRK1regulation and functions are mostly plant-specific and include activation by sucrose,phosphorylation of plant enzymes, and activa-tion of starch synthesis in potato tubers (50).Possibly because of a key role in starch ac-cumulation, SnRK1 silencing by DNA bom-bardment causes abnormal pollen develop-ment and male sterility in transgenic barley(155). Remarkably, significant differences ap-pear to exist between the activation mech-anisms for plant SnRKs, yeast Snf1, andmammalian AMPKs (50).

Modulation of Enzymatic Activityand Protein Degradation

Two SnRKs from spinach leaf can, in vitro,phosphorylate and inactivate 3-hydroxy-3-methylglutaryl-CoA reductase, nitrate reduc-tase (NR), and SPS, enzymes involved inisoprenoid synthesis, nitrogen assimilation,

Redox regulation:signals generated bythe photosyntheticelectron transportchain, transmitted tothioredoxins, canmodify targetenzymes bydisulphide bondreduction

and sucrose biosynthesis, respectively (126).The activation state of NR is associated withphotosynthetic activity and sugar availabil-ity. This observation offers a mechanism forSnRKs to coordinate carbon and nitrogenmetabolism. SnRK1s have overlapping sub-strate specificities with CDPKs, and detailedphosphorylation studies with synthetic pep-tides have defined the minimal recognition se-quence and the differential effects of specificresidues and their positions on activity andspecificity (57). Phosphorylation by SnRKsor CDPKs is, however, not always sufficientfor enzyme inactivation. Phosphorylation ofNR creates a phosphopeptide motif for 14-3-3 protein binding. This motif is responsi-ble for the actual reversible inhibition of en-zyme activity under stress conditions. Severalother metabolic enzymes have been shown tobind 14-3-3 proteins, including a TPS (90),and 14-3-3 proteins have been implicated incell survival under stress conditions. Severalkey metabolic enzymes, like NR, have rathershort half-lives and phosphorylation and 14-3-3 protein binding appears to be important incontrolling protein degradation as well. How-ever, there are contradictory results and inter-pretations as to the exact function of 14-3-3protein binding in protein degradation (63).Although some evidence indicates that 14-3-3 protein binding initiates and/or acceler-ates NR degradation, selective loss of 14-3-3protein binding appears to regulate cleavageof their binding partners, including NR andSPS, in sugar-starved Arabidopsis cells (27).

In addition to phosphorylation or de-phosphorylation and protein stability orbreakdown, redox regulation is emerging asanother important post-translational mecha-nism in sugar control of plant metabolism.This mechanism is well known to be involvedin reversible light-activation of key photo-synthetic enzymes, but is now also found toregulate plastid enzymes in nongreen het-erotrophic organs as well. Studies with potatotuber AGPase demonstrated that redox acti-vation of the enzyme (by reducing a disul-phide bond between two subunits of the

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tetrameric protein) regulates starch synthesisin response to sucrose import (135). Redoxactivation of AGPase is also observed aftersupplying exogenous sucrose to Arabidopsisleaves in the dark, or in a sugar accumulat-ing pgm mutant (53). Two different signal-ing pathways have been proposed for sucroseand glucose, involving SnRK1 and HXK, re-spectively (42, 135). Glucose feeding, throughHXK–dependent metabolism (e.g., the ox-idative pentose-P cycle), increases the over-all NADPH/NADP+ ratio, which then mostlikely increases the reduction state of the plas-tid thioredoxins. Unlike glucose, sucrose ac-tivation of AGPase is strongly attenuated inSnRK1-antisense potato tubers and can bemimicked by the nonmetabolizable sucrose-analog, palatinose. Although the exact signal-ing mechanism is not clear, this phenomenonappears to be another sucrose-specific signal-ing effect.

Gene Expression Regulation

SnRK1, like Snf1 and AMPK, also affects geneexpression. Antisense knockdown of SnRK1in potato, for example, causes a significantreduction in SUS4 gene expression in tu-bers and loss of SUS4 sucrose-inducibilityin leaves (106). This result is, however, notconsistent with a role for SnRK1 in sugarstarvation. It is proposed that SnRK1 canbe activated by high cellular sucrose and/orlow cellular glucose levels (50), although su-crose is hydrolyzed to glucose and fruc-tose in plant cells. Expression of the wheatαAMY2, is induced by carbon starvation incultured embryos, and SnRK1 antisense si-lencing represses transient αAMY2 promoteractivity (72). Although a prominent role forSnRK1 in plant metabolic signaling is nowgenerally accepted, there are often seem-ingly conflicting results. Possibly, SnRK1 reg-ulation and function differ depending onthe cell or tissue type, developmental stage,and on the interactions with other signalingmechanisms.

Regulation of SnRK1

SnRK1 kinase activity is controlled by phos-phorylation of a conserved threonine in theso-called activation or “T-loop” of the cat-alytic subunit. No upstream kinases or phos-phatases have been identified in plants yet.Unlike AMPK, SnRK1 is not allostericallyactivated by AMP. However, T-loop dephos-phorylation and consequent inactivation is in-hibited by binding of low, physiological con-centrations of 5′-AMP to SnRK1 (125). Alsoconsistent with a role in sugar starvation con-ditions, sugar phosphates, especially G6P, caninhibit SnRK1 activity (136). Similar to theyeast Snf1 and mammalian AMPKs, SnRK1sare heterotrimeric proteins. The associationof the catalytic α-subunits in complexes withdifferent regulatory β- and γ-subunits, differ-entially regulated by hormonal and environ-mental signals, cell and tissue type, and devel-opmental stage, offers another mechanism forcomplex and dynamic activity regulation andsignal integration.

In plants, SnRK1s interact with severalmore proteins. Pleiotropic Regulatory Lo-cus1 (PRL1) is a nuclear WD (Trp Asp) repeatprotein that interacts with the ArabidopsisSnRK1s (10). The prl1 mutant displays com-plex phenotypes, including transcriptionalderepression of glucose-responsive genesbut hypersensitivity to sugar and multiplehormones as well as hyperaccumulation offree sugars and starch. In a kinase assayusing immunoprecipitated protein complexesfrom Arabidopsis and an SPS peptide sub-strate, both sucrose and the prl1 mutationincreased SnRK1 activity. These data againchallenge the idea for a role of SnRK1 insugar starvation conditions. An in vitro assaywith purified proteins confirms that PRL1indeed acts as a negative regulator of SnRK1.However, although low glucose levels en-hance the yeast two-hybrid interaction withPRL1, the sucrose regulation of SnRK1activity is unaffected in prl1 mutant plants(10). Apparently, other factors or regulatorymechanisms are also involved.

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Partly explaining the complex andpleiotropic phenotypes, and possibly provid-ing a direct mechanistic link with metabolicregulation of protein degradation, the Ara-bidopsis SnRK1 is found to interact withboth the SCF ubiquitin E3 ligase subunitSKP1/ASK1 and the SKP1/ASK1-binding26S proteasome subunit α4/PAD1 (37).SKP1/ASK1 is also found in SCF complexesinvolved in the regulation of auxin andjasmonate signaling and senescence (122).In vitro, binding of SKP1/ASK1 to SnRK1increases under low glucose conditions andcompetes with PRL1 binding to the sameregulatory domain of SnRK1. In vivo, how-ever, they do not seem to occur in commonSnRK1 complexes (37). Further experimentsconfirm that SnRK1 associates with the 26Sproteasome. The exact relevance of thisinteraction is not clear.

Diverse SnRK1-interacting proteins(SnIPs) have been identified using yeast two-hybrid screening. It remains to be learnedwhether these SnIPs are regulators or targets.A novel protein tyrosine phosphatase (PTP),dubbed PTPKIS, has been shown to interactwith SnRK1 via a kinase interaction sequence(KIS) domain (39). The barley endospermclass I heat shock protein BHSP17 is aphosphorylation substrate of spinach leaf andbarley endosperm SnRK1 (121), providing anobvious link with a general stress response.More specifically, the geminivirus proteinsAL2 and L2 interact with and inactivatetobacco SnRK1. The metabolic alterationsmediated by SnRK1 may be a component ofthe plant’s antiviral defense mechanism (52).

In a screen for heterologous multicopysuppressors of the yeast snf4 (Snf1 regula-tory protein) deficiency, several proteins in-cluding a plant casein kinase I ortholog andtwo Msn2/4-type zinc-finger factors, AZF2and ZAT10, involved in stress responses, wereisolated in addition to the Arabidopsis Snf4 or-tholog (66).

The moss Physcomitrella patens (Pp) is an ex-cellent model system for functional genomicsbased on targeted gene knockouts. A moss Pp-

snf1a Ppsnf1b double knockout mutant, whichlacks all SnRK1 activity, displays abnormal de-velopment with premature senescence, hyper-sensitivity to auxin, and hyposensitivity to cy-tokinin. The mutant is unable to grow in lowlight or day/night light cycles, but the growthdefect can be partially rescued by supplemen-tation of an external carbon source, indicatingthat the moss SnRK1 is required for survivalunder low-energy conditions (129). The func-tion of SnRK1 in legume seeds is also beingcharacterized by gene silencing and microar-rays (146). Recent analysis of akin10 akin11double knockout in Arabidopsis leaves has re-vealed a central role of SnRK1 as a masterregulator in the stress and starvation signalingnetwork (F. Rolland, E. Baena-Gonzalez & J.Sheen, unpublished observations). Althougha conserved function for Snf1/AMPK/SnRK1in eukaryotic nutrient stress signaling appearsto be established, their regulation, down-stream targets, and interactions with otherpathways are likely more divergent. More re-search is needed to resolve the complex issuesof SnRK1 regulation and functions in flower-ing plants.

TREHALOSE

It is often difficult to determine at which levelsugar metabolism affects signal transduction(112). In plants, as in yeast and mammals,metabolic intermediates or alterations in cel-lular energy or redox state can also act assignals.

The ample examples of substrate and al-losteric feedback and feed-forward regulationof carbon metabolism by metabolic interme-diates, although important, are not a topic ofthis review. However, trehalose metabolism, asmall side-branch of the major carbon flux inbacterial, yeast, and plant cells, has recentlydrawn a lot of attention because of its in-triguing regulatory effects on plant growth,development, and stress resistance. The dis-accharide trehalose is typically synthesized ina two-step reaction: T6P is first synthesizedfrom G6P and UDP-Glc by TPS, and then

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TPP: trehalose-6-Pphosphatase

dephosphorylated to trehalose by a T6P phos-phatase (TPP). T6P levels are tightly regu-lated in yeast by a complex of the TPS (Tps1)and TPP (Tps2) proteins, together with aregulatory protein (redundantly encoded byTSL1 and TPS3). In Arabidopsis, addition ofeven fairly low amounts of external trehaloseto the growth medium results in a significantinhibition of seedling root elongation (149).Although its specificity is not well defined,the potent trehalase inhibitor validamycin hasbeen used to exclude possible effects of tre-halose hydrolysis to glucose. The growth de-fect on external trehalose is associated with astrong induction of the AGPase gene APL3,increased AGPase activity, and concomitanthyperaccumulation of starch in the cotyle-dons. This suggests that a failing allocationof photosynthate to the roots is causing thegrowth defect (149). Consistent with that hy-pothesis, addition of metabolizable sugars cansuppress the growth inhibition by trehalose.

In contrast to microorganisms, and withthe exception of some desert resurrectionplants like the pteridophyte Selaginella lepido-phylla [in which the high trehalose concen-trations (up to 15% of the dry weight) havebeen associated with extreme drought toler-ance], plants in general do not accumulate tre-halose at all. This can be explained partly bythe high trehalase activity that is likely alsoinvolved in exogenous trehalose breakdownduring symbiotic and pathogenic interactionswith microorganisms. However, introductionof yeast and bacterial trehalose synthesis genescan improve abiotic stress resistance signifi-cantly, albeit without increasing endogenoustrehalose concentrations to the extend foundin microorganisms; thus, this result is incon-sistent with a function for trehalose as a com-patible solute/stress protectant (reviewed inReference 99). In addition, whereas heterol-ogous alteration of trehalose metabolism typ-ically leads to clear morphological changes,regulated bacterial TPS-TPP coexpression orexpression of a bacterial TPSP (TPS-TPP)fusion construct abolishes these morpholog-

ical side effects (99). These observations allpoint to an important regulatory function.

Current attention has shifted to endoge-nous plant trehalose metabolism and its rolein growth and development, and heterolo-gous yeast tps1� mutant complementationhas identified functional plant TPS genesRemarkably, AtTPS1 is essential for embryomaturation. Arabidopsis tps1 knockout mutantsare developmentally arrested in the torpedostage, a phase in embryo development thatis generally associated with an increase insucrose levels and initiation of storage re-serve accumulation (35). It has been pro-posed that trehalose metabolism may be im-portant for the regulation of storage reserveaccumulation. However, using reserve pro-tein promoter-reporters and transcriptomic,metabolite, and microscopic analyses, it isfound that the actual cellular differentiationof the torpedo stage tps1 embryos resemblesthat of a equally old, cotyledon-stage wild-type embryo. This observation indicates thatmorphogenesis (cell growth and division) isaffected but uncoupled from differentiation(49). Expression of a bacterial TPS (OtsA) butnot the addition of trehalose could rescue theembryo-lethal mutants (117), pointing to theimportance of the T6P intermediate in devel-opment.

Controlled alterations of T6P levels byexpressing combinations of E. coli trehalosemetabolism genes clearly demonstrate thatT6P is indispensable for carbohydrate utiliza-tion for growth in Arabidopsis (117). Moreover,dexamethasone-induced expression of TPS1allows recovery of mature homozygous tps1mutant plants, showing that T6P is essen-tial for both normal vegetative growth andthe transition to flowering (141). Trehalose-mediated growth inhibition of seedlings is alsolikely due to T6P accumulation (118). The ex-act mechanism of T6P action, however, is stillunclear, since, unlike in yeast, T6P is not aninhibitor of plant HXK activity (35).

Surprisingly, but consistent with an im-portant regulatory role in growth and devel-opment, a plethora of trehalose metabolism

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genes is now being uncovered in plants (77,118, 143). There are four TPS1 (class I TPS;AtTPS1-4) and seven TPS2 (class II TPS withtwo C-terminal phosphatase boxes; AtTPS5-11) homologs in Arabidopsis. No TPS or TPPactivity has been detected yet for the classII proteins. Ten putative T6P phosphatase(AtTPPA-AtTPPJ) genes are annotated thatbasically contain only the phosphatase boxdomain. Although some have been shown tocomplement a yeast tps2� mutant, it is notclear how specific they are. Plants do notappear to have a TSL1-TPS3-like regula-tory subunit, required for complex formationin yeast. Interestingly, expression of the tre-halose metabolism genes is differentially reg-ulated during embryo development and senes-cence and by nitrogen and sugar availability,hypoxia, circadian rhythm, ABA, and exter-nal trehalose. A microarray analysis of theplant’s response to exogenous trehalose (118)has identified target genes mostly involvedin stress signaling. AKIN11 is also upregu-lated by trehalose, and its expression seems tocorrelate with T6P levels. Interestingly, T6Pregulates starch synthesis via redox activationof AGPase downstream of SnRK1 (69). Sev-eral Arabidopsis TPS proteins possess multi-ple SnRK1 phosphorylation sites revealed bya recent study using a novel multiparallel ki-nase target assay (47). AKIN10 overexpres-sion also induces class II TPS gene expression(F. Rolland & E. Baena-Gonzalez, unpub-lished observations).

TPS and TPP expression occurs in a widerange of tissues. Remarkably, the Arabidopsisclass II TPS genes show a cell layer-specificexpression in root and shoot apical meris-tems (M. Ramon, personal communication).This suggests a prominent role in growthregulation. It remains unclear how trehalosemetabolism affects growth and developmentand stress resistance. As in yeast, trehalosemetabolism likely interferes with sugar signal-ing in plants. Arabidopsis plants overexpress-ing the yeast TPS1 are drought tolerant andinsensitive to sugar and ABA, suggesting arole for TPS1 or its product in downregu-

lating HXK-dependent signaling (6). In ad-dition to trehalose, some plant and bacte-rial species accumulate fructose oligomers andpolymers, called fructans, as a reserve car-bohydrate that can enhance plant cold anddrought tolerance. The occurence of fruc-tan exohydrolases (FEHs) in non-fructan-accumulating plants such as Arabidopsis sim-ilarly suggests a defense-related role for theseenzymes (by acting on bacterial fructans) orthe presence of undetected low amounts ofendogenous fructans with a role as signalingmolecules (140).

CONCLUSIONS ANDPERSPECTIVES

Sugars are finally being recognized as impor-tant regulatory molecules with signaling func-tions in plants and other organisms. Whereasthe power of yeast genetics has enabled therapid and detailed elucidation of diverse sugarsensing and signaling pathways, plant sugarsignaling has proven more difficult to studydue to the complexity of source-sink interac-tions, responses to diverse sugar signals andmetabolites, and the intimate integration of aweb-like signaling network governed by planthormones, nutrients, and environmental con-ditions. The use of different experimental sys-tems, including isolated cells, excised tissues,cell cultures, whole plants, and mutants underdifferent environmental and nutrient condi-tions at various developmental stages is criticalin dissecting the plethora of sugar responsesand their connections in plants. Microarrayand clustering analysis are new, powerful ge-nomic tools to provide a global view on thetranscript dynamics controlled by differentsugar responses and identify novel regulatorycomponents and target genes. The sharing ofthe massive data sets is beginning to providenew insights into the extent and mechanismsof sugar-regulated gene expression and inter-actions with other signals. The molecular de-tails of signal transduction pathways and theircrosstalk with other pathways will be revealedby using a combination of genomic proteomic

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and genetic approaches. Current technol-ogy limits the ability to visualize and quan-tify the precise location and concentration ofvarious sugar molecules and metabolites inliving cells. Novel molecular sensors and fluo-

rescence resonance energy transfer (FRET)-based imaging (81) will hopefully circumventthis limitation and provide critical informa-tion to facilitate the elucidation of intracellu-lar sugar signal transduction pathways.

SUMMARY POINTS

1. Yeast is an excellent model and tool to study the conserved mechanisms of eukaryoticsugar sensing and signaling.

2. In plants, sugars control metabolism, growth, stress responses, and development fromembryogenesis to senescence.

3. Plant sugar regulation is mediated by diverse sugar signals, which are generated atdifferent locations depending on environmental conditions and developmental stage.Sucrose transport and hydrolysis play key regulatory roles in sugar signal generation.

4. Plant-specific sugar signaling mechanisms involve extensive interactions with planthormone signaling.

5. HXKs are evolutionarily conserved eukaryotic glucose sensors. Plants may also usemembrane receptors for extracellular sugar sensing.

6. Sugars regulate cellular activity at mutiple levels, from transcription and translationto protein stability and activity.

7. SnRK1s appear to play a conserved role in starvation responses, but are likely regu-lated differently in yeast, mammals and plants. Future studies will clarify the uniqueregulation of SnRK1s by sucrose and their critical role in cellular stress signaling, aswell as novel functions in the regulation of the daily cycle of carbon metabolism inplants.

8. Trehalose metabolism is emerging as a novel, important regulator of plant growth,metabolism, and stress resistance.

ACKNOWLEDGMENTS

We would like to thank Malcolm Campbell, Mark Stitt, Chris Leaver, Kenzo Nakamura,Wolf Frommer, Hai Huang, Jong-Seong Jeon, Alan Jones, Matthew Ramon, Brandon Moore,Young-Hee Cho, Sang-Dong Yoo, Qi Hall, and Wan-Hsing Cheng for sharing information. Weapologize for not citing many publications due to space limitations and refer to previous reviewsand more recent papers for detailed information. Research on sugar sensing and signaling inthe Sheen lab is currently supported by the NSF (IBN-02,17191) and NIH (R01 GM060493)grants. F.R. is supported by a return grant from the Belgian Office for Scientific, Technicaland Cultural Affairs and a fellowship from the Research Foundation – Flanders (FWO –Vlaanderen).

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2879. Lloyd JC, Zakhleniuk OV. 2004. Responses of primary and secondary metabolism to

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This paperdiscusses thedevelopment ofmolecular sensorsfor live imaging ofmetabolites,enabling the studyof metabolicsignaling withsubcellularresolution.

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85. Loreti E, Poggi A, Novi G, Alpi A, Perata P. 2005. A genome-wide analysis of theeffects of sucrose on gene expression in Arabidopsis seedlings under anoxia. Plant Physiol.137:1130–38

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300:332–36

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90. Moorhead G, Douglas P, Cotelle V, Harthill J, Morrice N, et al. 1999. Phosphorylation-dependent interactions between enzymes of plant metabolism and 14-3-3 proteins. PlantJ. 18:1–12

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One of the firstcomprehensivewhole-genomemicroarray analysesof Arabidopsis

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126. Sugden C, Donaghy PG, Halford NG, Hardie DG. 1999. Two SNF1-related proteinkinases from spinach leaf phosphorylate and inactivate 3-hydroxy-3-methylglutaryl-coenzyme A reductase, nitrate reductase, and sucrose phosphate synthase in vitro. PlantPhysiol. 120:257–74

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127. Sun C, Palmqvist S, Olsson H, Boren M, Ahlandsberg S, Jansson C. 2003. A novelWRKY transcription factor, SUSIBA2, participates in sugar signaling in barley by bind-ing to the sugar-responsive elements of the iso1 promoter. Plant Cell 15:2076–92

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130. Thibaud MC, Gineste S, Nussaume L, Robaglia C. 2004. Sucrose increasespathogenesis-related PR-2 gene expression in Arabidopsis thaliana through an SA-dependent but NPR1-independent signaling pathway. Plant Physiol. Biochem. 42:81–88

131. Thimm O, Blasing O, Gibon Y, Nagel A, Meyer S, et al. 2004. MAPMAN: a user-driven tool to display genomics data sets onto diagrams of metabolic pathways andother biological processes. Plant J. 37:914–39

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133. Thum KE, Shasha DE, Lejay LV, Coruzzi GM. 2003. Light- and carbon-signalingpathways. Modeling circuits of interactions. Plant Physiol. 132:440–52

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135. Tiessen A, Prescha K, Branscheid A, Palacios N, McKibbin R, et al. 2003. Evidence thatSNF1-related kinase and hexokinase are involved in separate sugar-signalling pathwaysmodulating post-translational redox activation of ADP-glucose pyrophosphorylase inpotato tubers. Plant J. 35:490–500

136. Toroser D, Plaut Z, Huber SC. 2000. Regulation of a plant SNF1-related protein kinaseby glucose-6-phosphate. Plant Physiol. 123:403–12

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144. Wang R, Okamoto M, Xing X, Crawford NM. 2003. Microarray analysis of the nitrateresponse in Arabidopsis roots and shoots reveals over 1,000 rapidly responding genesand new linkages to glucose, trehalose-6-phosphate, iron, and sulfate metabolism. PlantPhysiol. 132:556–67

145. Weber AP, Schwacke R, Flugge UI. 2005. Solute transporters of the plastid envelopemembrane. Annu. Rev. Plant Biol. 56:133–64

A nice overview ofthe centralregulatory role anddynamics of sugarmetabolism duringlegume seeddevelopment, withimportantimplications forsugar regulation ofwhole-plantdevelopment.

146. Weber H, Borisjuk L, Wobus U. 2005. Molecular physiology of legume seeddevelopment. Annu. Rev. Plant Biol. 56:253–79

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147. Wiese A, Elzinga N, Wobbes B, Smeekens S. 2004. A conserved upstream openreading frame mediates sucrose-induced repression of translation. Plant Cell

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This paperdescribes themolecular linkbetween glucoseand ethylenesignaling and theremarkableobservation thatplant HXK1 cantranslocate to thenucleus.

152. Yanagisawa S, Yoo SD, Sheen J. 2003. Differential regulation of EIN3 stability byglucose and ethylene signalling in plants. Nature 425:521–25

153. Yoshida S, Ito M, Nishida I, Watanabe A. 2002. Identification of a novel geneHYS1/CPR5 that has a repressive role in the induction of leaf senescence and pathogen-defence responses in Arabidopsis thaliana. Plant J. 29:427–37

154. Yu SM. 1999. Cellular and genetic responses of plants to sugar starvation. Plant Physiol.121:687–93

155. Zhang Y, Shewry PR, Jones H, Barcelo P, Lazzeri PA, Halford NG. 2001. Expressionof antisense SnRK1 protein kinase sequence causes abnormal pollen development andmale sterility in transgenic barley. Plant J. 28:431–41

156. Zhou L, Jang JC, Jones TL, Sheen J. 1998. Glucose and ethylene signal transductioncrosstalk revealed by an Arabidopsis glucose-insensitive mutant. Proc. Natl. Acad. Sci.USA 95:10294–99

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Annual Reviewof Plant Biology

Volume 57, 2006Contents

Looking at Life: From Binoculars to the Electron MicroscopeSarah P. Gibbs � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

MicroRNAs and Their Regulatory Roles in PlantsMatthew W. Jones-Rhoades, David P. Bartel, and Bonnie Bartel � � � � � � � � � � � � � � � � � � � � � � � � � �19

Chlorophyll Degradation During SenescenceS. Hortensteiner � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �55

Quantitative Fluorescence Microscopy: From Art to ScienceMark Fricker, John Runions, and Ian Moore � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �79

Control of the Actin Cytoskeleton in Plant Cell GrowthPatrick J. Hussey, Tijs Ketelaar, and Michael J. Deeks � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 109

Responding to Color: The Regulation of Complementary ChromaticAdaptationDavid M. Kehoe and Andrian Gutu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 127

Seasonal Control of Tuberization in Potato: Conserved Elements withthe Flowering ResponseMariana Rodríguez-Falcón, Jordi Bou, and Salomé Prat � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 151

Laser Microdissection of Plant Tissue: What You See Is What You GetTimothy Nelson, S. Lori Tausta, Neeru Gandotra, and Tie Liu � � � � � � � � � � � � � � � � � � � � � � � � � � 181

Integrative Plant Biology: Role of Phloem Long-DistanceMacromolecular TraffickingTony J. Lough and William J. Lucas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 203

The Role of Root Exudates in Rhizosphere Interactions with Plantsand Other OrganismsHarsh P. Bais, Tiffany L. Weir, Laura G. Perry, Simon Gilroy,

and Jorge M. Vivanco � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 233

Genetics of Meiotic Prophase I in PlantsOlivier Hamant, Hong Ma, and W. Zacheus Cande � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 267

Biology and Biochemistry of GlucosinolatesBarbara Ann Halkier and Jonathan Gershenzon � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 303

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Bioinformatics and Its Applications in Plant BiologySeung Yon Rhee, Julie Dickerson, and Dong Xu � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 335

Leaf HydraulicsLawren Sack and N. Michele Holbrook � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 361

Plant Uncoupling Mitochondrial ProteinsAnıbal Eugenio Vercesi, Jiri Borecky, Ivan de Godoy Maia, Paulo Arruda,

Iolanda Midea Cuccovia, and Hernan Chaimovich � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 383

Genetics and Biochemistry of Seed FlavonoidsLoıc Lepiniec, Isabelle Debeaujon, Jean-Marc Routaboul, Antoine Baudry,

Lucille Pourcel, Nathalie Nesi, and Michel Caboche � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 405

Cytokinins: Activity, Biosynthesis, and TranslocationHitoshi Sakakibara � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 431

Global Studies of Cell Type-Specific Gene Expression in PlantsDavid W. Galbraith and Kenneth Birnbaum � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 451

Mechanism of Leaf-Shape DeterminationHirokazu Tsukaya � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 477

Mosses as Model Systems for the Study of Metabolism andDevelopmentDavid Cove, Magdalena Bezanilla, Phillip Harries, and Ralph Quatrano � � � � � � � � � � � � � � 497

Structure and Function of Photosystems I and IINathan Nelson and Charles F. Yocum � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 521

Glycosyltransferases of Lipophilic Small MoleculesDianna Bowles, Eng-Kiat Lim, Brigitte Poppenberger, and Fabian E. Vaistij � � � � � � � � � � � 567

Protein Degradation Machineries in PlastidsWataru Sakamoto � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 599

Molybdenum Cofactor Biosynthesis and Molybdenum EnzymesGunter Schwarz and Ralf R. Mendel � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 623

Peptide Hormones in PlantsYoshikatsu Matsubayashi and Youji Sakagami � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 649

Sugar Sensing and Signaling in Plants: Conserved and NovelMechanismsFilip Rolland, Elena Baena-Gonzalez, and Jen Sheen � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 675

Vitamin Synthesis in Plants: Tocopherols and CarotenoidsDean DellaPenna and Barry J. Pogson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 711

Plastid-to-Nucleus Retrograde SignalingAjit Nott, Hou-Sung Jung, Shai Koussevitzky, and Joanne Chory � � � � � � � � � � � � � � � � � � � � � � 739

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The Genetics and Biochemistry of Floral PigmentsErich Grotewold � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 761

Transcriptional Regulatory Networks in Cellular Responses andTolerance to Dehydration and Cold StressesKazuko Yamaguchi-Shinozaki and Kazuo Shinozaki � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 781

Pyrimidine and Purine Biosynthesis and Degradation in PlantsRita Zrenner, Mark Stitt, Uwe Sonnewald, and Ralf Boldt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 805

Phytochrome Structure and Signaling MechanismsNathan C. Rockwell, Yi-Shin Su, and J. Clark Lagarias � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 837

Microtubule Dynamics and Organization in the Plant Cortical ArrayDavid W. Ehrhardt and Sidney L. Shaw � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 859

INDEXES

Subject Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 877

Cumulative Index of Contributing Authors, Volumes 47–57 � � � � � � � � � � � � � � � � � � � � � � � � � � � 915

Cumulative Index of Chapter Titles, Volumes 47–57 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 920

ERRATA

An online log of corrections to Annual Review of Plant Biology chapters (if any, 1977 tothe present) may be found at http://plant.annualreviews.org/

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