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  • 10 Sep 2004 12:23 AR AR226-CB20-04.tex AR226-CB20-04.sgm LaTeX2e(2002/01/18) P1: GCE10.1146/annurev.cellbio.20.010403.105307

    Annu. Rev. Cell Dev. Biol. 2004. 20:87123doi: 10.1146/annurev.cellbio.20.010403.105307

    Copyright c 2004 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on April 21, 2004

    BI-DIRECTIONAL PROTEIN TRANSPORT BETWEENTHE ER AND GOLGI

    Marcus C.S. Lee,1 Elizabeth A. Miller,1Jonathan Goldberg,2 Lelio Orci,3 and Randy Schekman11Howard Hughes Medical Institute and Department of Molecular and Cell Biology,University of California, Berkeley, California; 2Howard Hughes Medical Institute andMemorial Sloan-Kettering Cancer Center, New York; 3Department of Morphology,University of Geneva Medical School, Switzerland; email: mcslee@uclink4.berkeley.edu;e miller@uclink4.berkeley.edu; jonathan@ximpact4.ski.mskcc.org;Lelio.Orci@medecine.unige.ch; schekman@uclink4.berkeley.eduThese authors contributed equally to this work

    Key Words vesicle transport, COPI, COPII, coat proteins, cargo selection

    Abstract The endoplasmic reticulum (ER) and the Golgi comprise the first twosteps in protein secretion. Vesicular carriers mediate a continuous flux of proteinsand lipids between these compartments, reflecting the transport of newly synthesizedproteins out of the ER and the retrieval of escaped ER residents and vesicle machinery.Anterograde and retrograde transport is mediated by distinct sets of cytosolic coatproteins, the COPII and COPI coats, respectively, which act on the membrane tocapture cargo proteins into nascent vesicles. We review the mechanisms that governcoat recruitment to the membrane, cargo capture into a transport vesicle, and accuratedelivery to the target organelle.

    CONTENTS

    INTRODUCTION TO THE SECRETORY PATHWAY . . . . . . . . . . . . . . . . . . . . . . . . 88GAINING TRANSPORT COMPETENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

    Folding and Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Accessing an Active Transport Zone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Bulk Flow Exit from the ER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Enrichment of Cargo Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

    GENERATING A VESICLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Coat Recruitment and Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Cargo Capture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

    DELIVERY OF VESICLES: MOTORS, TETHERING, AND FUSION . . . . . . . . . . 109Motor Proteins and Vesicle Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109Vesicle Tethering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110SNARE Assembly and Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

    NON-CANONICAL TRANSPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

    1081-0706/04/1115-0087$14.00 87

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    88 LEE ET AL.

    Anterograde Transport of Large Cargo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113COPI-Independent Retrograde Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

    CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

    INTRODUCTION TO THE SECRETORY PATHWAY

    Eukaryotic cells possess an elaborate endomembrane system that makes up thesecretory pathway (Figure 1). This network consists of a number of independentorganelles that function sequentially to effect protein secretion to the extracel-lular environment. Each compartment provides a specialized environment thatfacilitates the various stages in protein biogenesis, modification, sorting, and, ul-timately, secretion. The ER is the entry point into the secretory pathway for newlysynthesized proteins: Ribosomes dock onto a protein pore in the ER membrane,thereby releasing the nascent polypeptide into the lumen of the ER. The pri-mary role of the ER is to provide a milieu that facilitates protein folding. This isachieved by the presence of chaperones that massage a newly synthesized pro-tein into its correct conformation, sometimes through the catalysis of disulfidebond formation. Post-translational modification of nascent chains first occurs inthe ER, including addition of N-linked glycan chains and hydroxylation of prolineresidues.

    The next station that a folded secretory protein visits is the Golgi apparatus, aseries of cisternae housing enzymes that function in glycan side chain modifica-tion and proteolytic cleavage. The modification of carbohydrate moieties can beextensive and proceeds sequentially, with distinct glycosyltranferases specificallylocated to cis-, medial-, or trans-compartments of the Golgi. The trans-Golgi net-work (TGN) serves as a sorting station that either sends proteins to the cell sur-face or diverts them to additional compartments of the endomembrane system,

    Figure 1 Transport in the early secretory pathway. (a) Thin section electron micro-graph of an insulin-secreting cell. The ribosome-studded rough endoplasmic reticulum(ER) is visible, giving rise at one site to a budding profile (arrow). Such exit sites,also known as the transitional ER, produce numerous transport vesicles (TV) that willultimately be delivered to the stacked cisternae of the Golgi apparatus (Orci 1982).(b) Diagrammatic representation of ER-Golgi transport. COPII coat proteins medi-ate anterograde vesicle formation, selecting anterograde cargo and SNAREs. COPIIvesicles in plants and yeast fuse directly with the Golgi, but in mammalian cells theyseem to undergo homotypic fusion to generate a pleiomorphic structure known bothas the ER-Golgi intermediate compartment (ERGIC) and vesicular tubular clusters(VTC). The ERGIC/VTC is a site for concentrating retrograde cargo into COPI vesi-cles for delivery back to the ER. The ERGIC/VTC is delivered en bloc to the Golgi ina microtubule-dependent manner. Additional retrograde traffic from the Golgi properis also mediated by COPI vesicles.

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    ER-GOLGI TRANSPORT 89

    including the vacuole/lysosome, which is responsible for protein degradation, orto a variety of endosomal compartments that broadly function in protein sortingevents between the plasma membrane, TGN, and lysosome/vacuole.

    Transport of proteins between these various compartments of the secretory path-way largely occurs via small vesicles that are generated at a donor compartment

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    and fuse with a downstream acceptor compartment. Cytoplasmic coat proteinssculpt vesicles by locally deforming the donor membrane. Distinct sets of coatsfunction at different steps in the secretory pathway: Clathrin and its various adap-tors function in a number of transport events between the TGN, endosome, lyso-some/vacuole, and plasma membrane; the COPI coatomer complex functions inretrograde transport between the Golgi and ER; and the COPII coat delivers pro-teins from the ER to the Golgi. In addition to their role in vesicle formation, coatproteins also drive the selective capture of proteins into vesicles by interacting withspecific signals present on the cytoplasmic domains of proteins. The combinationof coat recruitment to the correct donor membrane and signal-specific interactionsbetween the coat and cargo proteins contributes to the directionality and fidelityof vesicular transport. Further transport specificity is imparted by specific combi-nations of tethering complexes and fusion assemblies known as SNAREs (solubleN-ethylmaleimide-sensitive factor attachment protein receptors), both of whichfacilitate fusion of vesicles with acceptor organelles.

    This review focuses on the mechanisms of vesicular transport between the firsttwo compartments of the secretory pathway, the ER and the Golgi. Transportbetween these organelles occurs in two directions: anterograde (ER-Golgi) trans-port delivers newly synthesized cargo proteins to the Golgi, whereas retrograde(Golgi-ER) tr

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