Redox Regulation of Transcription Factors in Plant Stress Acclimation and Development

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  • FORUM REVIEW ARTICLE

    Redox Regulation of Transcription Factorsin Plant Stress Acclimation and Development

    Karl-Josef Dietz

    Abstract

    Significance: The redox regulatory signaling network of the plant cell controls and co-regulates transcriptionalactivities, thereby enabling adjustment of metabolism and development in response to environmental cues,including abiotic stress. Recent Advances: Our rapidly expanding knowledge on redox regulation of planttranscription is driven by methodological advancements such as sensitive redox proteomics and in silico pre-dictions in combination with classical targeted genetic and molecular approaches, often in Arabidopsis thaliana.Thus, transcription factors (TFs) are both direct and indirect targets of redox-dependent activity modulation.Redox control of TF activity involves conformational switching, nucleo-cytosolic partitioning, assembly withcoregulators, metal-S-cluster regulation, redox control of upstream signaling elements, and proteolysis. CriticalIssues: While the significance of redox regulation of transcription is well established for prokaryotes and non-plant eukaryotes, the momentousness of redox-dependent control of transcription in plants still receives in-sufficient awareness and, therefore, is discussed in detail in this review. Future Directions: Improved proteomesensitivity will enable characterization of low abundant proteins and to simultaneously address the various post-translational modifications such as nitrosylation, hydroxylation, and glutathionylation. Combining suchapproaches by gradually increasing biotic and abiotic stress strength is expected to result in a systematicunderstanding of redox regulation. In the end, only the combination of in vivo, ex vivo, and in vitro results willprovide conclusive pictures on the rather complex mechanism of redox regulation of transcription. Antioxid.Redox Signal. 21, 13561372.

    The Redox Regulatory Network of the Cell

    Plants are structured from modules such as leaves,branches, side roots, flowers, and fruits. The number ofmodules developed during the plant life cycle varies. Thismodular characteristic enables plants to display an enormousmorphological plasticity in dependence on resource avail-ability and many other environmental parameters. Good en-vironmental conditions enable vigorous growth with manymodules, while adverse conditions delimit the number ofmodules. Complementary to the morphological plasticity,plants realize genetic and biochemical plasticity. By triggeringspecific gene expression programs and post-translationalstates, the genetic and biochemical plasticity enables an op-timization of acclimation responses to various types andcombinations of biotic and abiotic stress. Thus, plants accli-

    mate to the environment at different molecular levels by (i)rapid biochemical modulation of metabolism, (ii) just-in-timeactivation of cell defense (iii) transcriptional and translationalrearrangement of metabolism, (iv) long-term control of sizeand number of organs (modules), and (v) the timing of de-velopmental transitions. Levels (ii)(v) include gene expres-sion regulation. Optimized realization of metabolic anddevelopmental plasticity depends on a continuous sensing ofinternal and external parameters and appropriate adjustmentof the modular plant morphology within the preformed ge-netic and epigenetic program.

    A huge body of evidence proves that reactive oxygenspecies (ROS), reactive nitrogen species (RNS), and other re-dox cues participate in most, if not all, of these acclimationsteps. A significant part of cellular redox regulation targets thethiolome. In simple terms, the dynamic thiol state of a cell can

    Biochemistry and Physiology of Plants, Faculty of Biology, Bielefeld University, Bielefeld, Germany.

    ANTIOXIDANTS & REDOX SIGNALINGVolume 21, Number 9, 2014 Mary Ann Liebert, Inc.DOI: 10.1089/ars.2013.5672

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  • be defined as (i) the rate of sulfur assimilation; (ii) the levels ofthiols, including the small pool of free cysteine; the major low-molecular-mass thiol buffer glutathione (GSH) and the verylarge thiol pool in proteins, which together form the thiolome;(iii) the rate of sulfur diversion into other pathways; (iv) theelectron flux into the thiol network; and (v) the drainage ofelectrons from the network by oxidants such as ROS and RNS(Fig. 1). Thiols of the thiolome can undergo diverse modifi-cations, in particular conversion to the disulfide, sulfenic,sulfinic and sulfonic acid, nitrosothiol, and glutathionylatedforms (Fig. 1).

    For a long time, the symptoms associated with ROS accu-mulation were solely considered indicators of severe sick-ness and termed oxidative stress, indicating a pathologicalmisbalance between oxidant generation and antioxidantprovision. Nowadays, it has become clear that this view is anobsolete simplification. The signaling function of ROS hasemerged as a fundamental principle in cellular communica-tion (1), and the concept of the redox regulatory network ofthe cell has been developed as a central element in acclimation(22, 45). Arguments that are based on their reactivity and thevery high superoxide dismutase (SOD) activity support theview that radicals such as O2

    - , RO, Cl, and, possibly inmost cases, NO cannot function in specific signaling (8, 30).These reactive molecular species need to be detoxified, asotherwise they oxidize cell constituents in a rather non-specific manner. However, such highly reactive species mayact at a broader level as recognized by the identification ofS-nitrosylation as another commonly encountered post-translational modification (PTM) with yet insufficiently ex-plored functional implications (67, 96).

    Dielectron oxidants such as H2O2 usually react at very lowrates with protein thiols in their protonated state, while thethiolate anion of cysteine acts as a strong nucleophile andreadily reacts with oxidants. In a simple view, reactivity isinversely correlated with pK-value. Thus, thiols can be acti-vated by lowering the pKa through neighboring effects withinthe peptide decreasing the activation barrier. However, inaddition, diffuse electric fields, dipole properties, solvent ac-cessibility, and the neighboring hydrogen bond network alsoaffect thiol reactivity (28). As a consequence, each protein thiol

    and non-protein thiol may react specifically. In addition,many regulatory feedback loops control redox homeostasisand ROS generation of the cell (Fig. 2A) (101). All thesefunctional dependencies suggest that oxidative stress isreadout of deregulated signaling pathways (40), while thegeneration of ROS and RNS, first of all, is a mechanism that isused to adjust the redox state of the redox regulatory networkof the cell with all its signaling requirements. They also tunegene transcription.

    Six functional elements co-operate in the redox regulatorynetwork, which is essentially conserved throughout all or-ganisms. These network elements are commonly found incytosol, nucleoplasm, mitochondrion, and plastids.

    (i) Redox input elements link redox reactions of metabolismto redox regulation of protein thiols. They feed electrons intothe regulatory redox network. NADPH in combination withNADPH-dependent thioredoxin reductase, ferredoxin (Fd)along with Fd-dependent thioredoxin reductase, and gluta-thione reductase (GR)/GSH are the dominating redox inputelements in plants (Fig. 2B).

    (ii) Redox transmitters transfer and distribute electrons fromthe input elements to downstream target proteins. Thesefamilies of proteins are particularly enlarged in plants withnearly 44 thioredoxins (Trx) and Trx-like proteins and 33glutaredoxins (Grxs) that are encoded in the Arabidopsisthaliana genome (45). Grx are grouped according to their se-quence similarities that correlate with the reaction mechanismin deglutathionylation by the monothiol- or dithiol mecha-nism or as disulfide reductase (111). They have specific sub-cellular localization, for example, Trx-h is also found in thenucleus of seeds (105).

    (iii) Redox target proteins display redox-sensitive thiolswhose redox state is controlled by redox transmitters. Morethan 400 target proteins have tentatively been identified byvarious targeted and screening approaches, as summarized inrecent reviews (10, 66, 110). The drawback of the screeningapproaches (redox proteomics) is that mostly the abundantcellular thiol-disulfide redox proteins are identified. Thelimitation of the targeted approaches is their focus on usuallysingle proteins. However, it will be shown next that an in-creasing number of important players of less abundant

    FIG. 1. The dynamic redox thiolome of thecell. The thiolome is defined by the rate of thiolsynthesis , the total redox-active thiol pool(gray box), including Cys, GSH, and proteinthiols , the withdrawal of sulfur from the pool

    , the rate of electron influx , and the efflux tofinal electron acceptors such as ROS and RNS .It should be noted that only a part of the totalpool of theoretically available protein thiols is,indeed, redox active. The arrows mark relation-ships, but are far from complete; for example, amajor route to protein thiol reduction is realizedby the vast number of thioredoxins as redoxtransmitters. The list on the left hand sideindicates commonly encountered PTMs ofthiol groups, namely disulfide, sulfenic, sulfinic,and sulfonic acid, S-nitrosylation and S-glutathionylation. GSH, glutathione; PTM,post-translational modification; RNS, reactivenitrogen species; ROS, reactive oxygen species.

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  • signaling elements have been identified and that the increasedsensitivity of redox proteomics opens the perspective to aglobal understanding of redox regulation. Redox targets havebeen assigned to most gene ontology groups, including met-abolic pathways, translation, and transcription. Interestingly,the energy-consuming process of translation is a prime targetof redox regulation (37).

    (iv) Redox buffer proteins were recently suggested to play animportant role in maintaining redox homeostasis in the thiol-disulfide network. Cysteines of ribulose-1,5-bisphosphatecarboxylase oxygenase (RubisCO) were identified as beingsensitive to early oxidation in vitro and in vivo (74, 79). Takinginto consideration the concentration of thiols in the large andsmall RubisCO subunits, the RubisCO thiol pool dominatesthe thiol redox buffer capacity of the chloroplast, exceedingthe thiols in GSH by more than one order. Thus, redox tran-sitions of RubisCO thiols appear to be important in catalyticregulation, control of turnover (74), and redox homeostasis ofthe chloroplast. Due to its high concentration, RubisCO maybe considered a special example; however, the hypothesisshould be tested in general, namely that protein thiols exert animportant function in transiently buffering redox imbalances.

    (v) Redox sensors deliver information on ROS/RNS levelsinto the redox regulatory network and realize cross-talk toother signaing pathways (Fig. 2C). One can distinguish be-tween kinetic and static redox sensors (21). Kinetic sensors area part of the electron flow within the signaling redox cascade,while the redox state of static sensors is adjusted in equilib-

    rium with elements of the redox cascade but themselves donot take part in electron flow. Kinetic sensors, for example,have a high affinity to ROS or RNS and turn oxidized if thereaction rate with ROS and RNS exceeds the rate of reductiveregeneration of the sensor. Direct oxidation of redox targetsinstead of indirect electron drainage by redox sensors neces-sitates that the reaction constants compete with those of per-oxiredoxins and GSH peroxidases. Otherwise, they will not beable to function as reliable redox sensors (8).

    (vi) Final electron acceptors are reactive low-molecular-massredox species (ROS, RNS, reactive sulfur species [RSS], andreactive carbonyl species [RCS]) (18). By abstracting electronsfrom appropriate donors, they finally reach the oxidationlevels of, for example, H2O, NO3

    - , and SO42 - , which are

    nonreactive. Superoxide and nitric oxide combine to formperoxinitrite, which is highly reactive. As rationalized byBrigelius-Flohe and Flohe (8), efficient final acceptors in ashort distance are NO and O2

    - among the free radicals, andefficient signaling components are H2O2 and alkyl hydro-peroxides.

    In evolutionary terms, the network components are likelyevolved as catalysts of redox reactions in metabolism such asthe reduction of desoxyribonucleotides to ribonucleotides,where redox co-substrates participate in the metabolic reac-tions (Fig. 3A) (33). Another redox pathway may have gainedfunction in feeding electrons in thiol antioxidants to decom-pose ROS and RNS when the atmospheric oxygen concen-tration was still low (Fig. 3B). It is proposed that subsequently,

    FIG. 2. Important reactions in thiol-disulfide regulation and function of redox sensors. (A) General structure of asignaling cascade linking metabolism to response. The example shows how wound-induced lipid peroxidation increaseslevels of OPDA, which bind to cyclophilin Cyp20-3 (88). The OPDA-liganded Cyp20-3 binds to serine acetyltransferase,which activates the cysteine synthase complex and results in enhanced Cys synthesis and improved redox homeostasis. (B)Redox input element, redox transmitter, and redox sensor. Exemplary reactions given here are the NTR, the thioredoxin-mediated disulfide reduction of a target protein (middle), and the peroxiredoxin with its deprotonated peroxidatic cysteinereacting with a peroxide (ROOH, R stands for H, alkyl, or ON in peroxinitrite) (45). (C) Distinction between static and kineticsensors. The kinetic sensor is a component of the thiol-disulfide/ROS redox cascade, while the static sensor equilibrates withthe redox state of another redox component and itself does not participate in the electron flow (21). Cyp20-3, stromalcyclophilin 20-3; NTR, NADPH-dependent thioredoxin reductase; OPDA, oxophytodienoic acid.

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  • a salvage pathway for the regeneration of oxidized intra- orintermolecular disulfide bridges or other oxidized speciesdeveloped as the oxygen concentration increased in the at-mosphere. An example is methionine sulfoxide reductase,which reduces oxidized sulfur in methionine and is linked toredox transmitters (17). In the third step, redox switchingbetween dithiol- and disulfide states may have enabled reg-ulation of protein function, in particular of enzyme activity(Fig. 3C). Such new regulatory mechanisms by post-transla-tional redox modification tightly and immediately linkedcellular redox state to metabolic activity. In the fourthstep, diversification of redox regulation occurred by geneduplications of redox transmitters and incorporation ofredox-sensitive domains in target proteins. The n...

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