The ERGIC (ER-to-Golgi intermediate compartment, also known as vesicular-tubular clusters, VTCs) is a stable, biochemically distinct compartment located adjacent to ER exit sites (Ben-Tekaya et al, 2005; reviewed in Szul and Sztul, 2011). The ERGIC concentrates COPII-derived cargo from the ER for further anterograde transport to the cis-Golgi and also recycles resident ER proteins back to the ER through retrograde traffic. Both of these pathways appear to make use of microtubule-directed COPI-coated vesicles (Pepperkok et al, 1993; Presley et al, 1997; Scales et al, 1997; Stephens and Pepperkok, 2002; Stephens et al, 2000; reviewed in Lord et al, 2001; Spang et al, 2013).
View original pathway at Reactome.
Weide T, Bayer M, Köster M, Siebrasse JP, Peters R, Barnekow A.; ''The Golgi matrix protein GM130: a specific interacting partner of the small GTPase rab1b.''; PubMedEurope PMCScholia
Wang H, Kazanietz MG.; ''Chimaerins, novel non-protein kinase C phorbol ester receptors, associate with Tmp21-I (p23): evidence for a novel anchoring mechanism involving the chimaerin C1 domain.''; PubMedEurope PMCScholia
Willett R, Ungar D, Lupashin V.; ''The Golgi puppet master: COG complex at center stage of membrane trafficking interactions.''; PubMedEurope PMCScholia
Monetta P, Slavin I, Romero N, Alvarez C.; ''Rab1b interacts with GBF1 and modulates both ARF1 dynamics and COPI association.''; PubMedEurope PMCScholia
Tanigawa G, Orci L, Amherdt M, Ravazzola M, Helms JB, Rothman JE.; ''Hydrolysis of bound GTP by ARF protein triggers uncoating of Golgi-derived COP-coated vesicles.''; PubMedEurope PMCScholia
Pepperkok R, Scheel J, Horstmann H, Hauri HP, Griffiths G, Kreis TE.; ''Beta-COP is essential for biosynthetic membrane transport from the endoplasmic reticulum to the Golgi complex in vivo.''; PubMedEurope PMCScholia
Allan BB, Moyer BD, Balch WE.; ''Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion.''; PubMedEurope PMCScholia
Beard M, Satoh A, Shorter J, Warren G.; ''A cryptic Rab1-binding site in the p115 tethering protein.''; PubMedEurope PMCScholia
Donaldson JG, Cassel D, Kahn RA, Klausner RD.; ''ADP-ribosylation factor, a small GTP-binding protein, is required for binding of the coatomer protein beta-COP to Golgi membranes.''; PubMedEurope PMCScholia
Ben-Tekaya H, Miura K, Pepperkok R, Hauri HP.; ''Live imaging of bidirectional traffic from the ERGIC.''; PubMedEurope PMCScholia
Südhof TC, Rothman JE.; ''Membrane fusion: grappling with SNARE and SM proteins.''; PubMedEurope PMCScholia
Shestakova A, Suvorova E, Pavliv O, Khaidakova G, Lupashin V.; ''Interaction of the conserved oligomeric Golgi complex with t-SNARE Syntaxin5a/Sed5 enhances intra-Golgi SNARE complex stability.''; PubMedEurope PMCScholia
Zhang T, Wong SH, Tang BL, Xu Y, Peter F, Subramaniam VN, Hong W.; ''The mammalian protein (rbet1) homologous to yeast Bet1p is primarily associated with the pre-Golgi intermediate compartment and is involved in vesicular transport from the endoplasmic reticulum to the Golgi apparatus.''; PubMedEurope PMCScholia
Xu Y, Martin S, James DE, Hong W.; ''GS15 forms a SNARE complex with syntaxin 5, GS28, and Ykt6 and is implicated in traffic in the early cisternae of the Golgi apparatus.''; PubMedEurope PMCScholia
Manolea F, Chun J, Chen DW, Clarke I, Summerfeldt N, Dacks JB, Melançon P.; ''Arf3 is activated uniquely at the trans-Golgi network by brefeldin A-inhibited guanine nucleotide exchange factors.''; PubMedEurope PMCScholia
Frigerio G, Grimsey N, Dale M, Majoul I, Duden R.; ''Two human ARFGAPs associated with COP-I-coated vesicles.''; PubMedEurope PMCScholia
Mayer A, Wickner W, Haas A.; ''Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles.''; PubMedEurope PMCScholia
Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE.; ''A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion.''; PubMedEurope PMCScholia
Popoff V, Adolf F, Brügger B, Wieland F.; ''COPI budding within the Golgi stack.''; PubMedEurope PMCScholia
Takida S, Maeda Y, Kinoshita T.; ''Mammalian GPI-anchored proteins require p24 proteins for their efficient transport from the ER to the plasma membrane.''; PubMedEurope PMCScholia
Szul T, Grabski R, Lyons S, Morohashi Y, Shestopal S, Lowe M, Sztul E.; ''Dissecting the role of the ARF guanine nucleotide exchange factor GBF1 in Golgi biogenesis and protein trafficking.''; PubMedEurope PMCScholia
Luo R, Ha VL, Hayashi R, Randazzo PA.; ''Arf GAP2 is positively regulated by coatomer and cargo.''; PubMedEurope PMCScholia
Waters MG, Serafini T, Rothman JE.; '''Coatomer': a cytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesicles.''; PubMedEurope PMCScholia
D'Souza-Schorey C, Chavrier P.; ''ARF proteins: roles in membrane traffic and beyond.''; PubMedEurope PMCScholia
Zolov SN, Lupashin VV.; ''Cog3p depletion blocks vesicle-mediated Golgi retrograde trafficking in HeLa cells.''; PubMedEurope PMCScholia
GarcÃa-Mata R, Sztul E.; ''The membrane-tethering protein p115 interacts with GBF1, an ARF guanine-nucleotide-exchange factor.''; PubMedEurope PMCScholia
Seemann J, Jokitalo EJ, Warren G.; ''The role of the tethering proteins p115 and GM130 in transport through the Golgi apparatus in vivo.''; PubMedEurope PMCScholia
Niu TK, Pfeifer AC, Lippincott-Schwartz J, Jackson CL.; ''Dynamics of GBF1, a Brefeldin A-sensitive Arf1 exchange factor at the Golgi.''; PubMedEurope PMCScholia
Zhao X, Claude A, Chun J, Shields DJ, Presley JF, Melançon P.; ''GBF1, a cis-Golgi and VTCs-localized ARF-GEF, is implicated in ER-to-Golgi protein traffic.''; PubMedEurope PMCScholia
Scales SJ, Pepperkok R, Kreis TE.; ''Visualization of ER-to-Golgi transport in living cells reveals a sequential mode of action for COPII and COPI.''; PubMedEurope PMCScholia
Godi A, Santone I, Pertile P, Devarajan P, Stabach PR, Morrow JS, Di Tullio G, Polishchuk R, Petrucci TC, Luini A, De Matteis MA.; ''ADP ribosylation factor regulates spectrin binding to the Golgi complex.''; PubMedEurope PMCScholia
Shah N, Colbert KN, Enos MD, Herschlag D, Weis WI.; ''Three αSNAP and 10 ATP molecules are used in SNARE complex disassembly by N-ethylmaleimide-sensitive factor (NSF).''; PubMedEurope PMCScholia
Lanoix J, Ouwendijk J, Stark A, Szafer E, Cassel D, Dejgaard K, Weiss M, Nilsson T.; ''Sorting of Golgi resident proteins into different subpopulations of COPI vesicles: a role for ArfGAP1.''; PubMedEurope PMCScholia
Aoe T, Cukierman E, Lee A, Cassel D, Peters PJ, Hsu VW.; ''The KDEL receptor, ERD2, regulates intracellular traffic by recruiting a GTPase-activating protein for ARF1.''; PubMedEurope PMCScholia
Ong YS, Tran TH, Gounko NV, Hong W.; ''TMEM115 is an integral membrane protein of the Golgi complex involved in retrograde transport.''; PubMedEurope PMCScholia
Luo W, Wang Y, Reiser G.; ''Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking.''; PubMedEurope PMCScholia
Szul T, Garcia-Mata R, Brandon E, Shestopal S, Alvarez C, Sztul E.; ''Dissection of membrane dynamics of the ARF-guanine nucleotide exchange factor GBF1.''; PubMedEurope PMCScholia
Otto H, Hanson PI, Jahn R.; ''Assembly and disassembly of a ternary complex of synaptobrevin, syntaxin, and SNAP-25 in the membrane of synaptic vesicles.''; PubMedEurope PMCScholia
Nakamura N, Lowe M, Levine TP, Rabouille C, Warren G.; ''The vesicle docking protein p115 binds GM130, a cis-Golgi matrix protein, in a mitotically regulated manner.''; PubMedEurope PMCScholia
Szul T, Sztul E.; ''COPII and COPI traffic at the ER-Golgi interface.''; PubMedEurope PMCScholia
Müller JM, Rabouille C, Newman R, Shorter J, Freemont P, Schiavo G, Warren G, Shima DT.; ''An NSF function distinct from ATPase-dependent SNARE disassembly is essential for Golgi membrane fusion.''; PubMedEurope PMCScholia
Sohda M, Misumi Y, Yoshimura S, Nakamura N, Fusano T, Ogata S, Sakisaka S, Ikehara Y.; ''The interaction of two tethering factors, p115 and COG complex, is required for Golgi integrity.''; PubMedEurope PMCScholia
Devarajan P, Stabach PR, De Matteis MA, Morrow JS.; ''Na,K-ATPase transport from endoplasmic reticulum to Golgi requires the Golgi spectrin-ankyrin G119 skeleton in Madin Darby canine kidney cells.''; PubMedEurope PMCScholia
Eugster A, Frigerio G, Dale M, Duden R.; ''COP I domains required for coatomer integrity, and novel interactions with ARF and ARF-GAP.''; PubMedEurope PMCScholia
Kahn RA, Bruford E, Inoue H, Logsdon JM, Nie Z, Premont RT, Randazzo PA, Satake M, Theibert AB, Zapp ML, Cassel D.; ''Consensus nomenclature for the human ArfGAP domain-containing proteins.''; PubMedEurope PMCScholia
Volpicelli-Daley LA, Li Y, Zhang CJ, Kahn RA.; ''Isoform-selective effects of the depletion of ADP-ribosylation factors 1-5 on membrane traffic.''; PubMedEurope PMCScholia
Reinhard C, Harter C, Bremser M, Brügger B, Sohn K, Helms JB, Wieland F.; ''Receptor-induced polymerization of coatomer.''; PubMedEurope PMCScholia
Sönnichsen B, Lowe M, Levine T, Jämsä E, Dirac-Svejstrup B, Warren G.; ''A role for giantin in docking COPI vesicles to Golgi membranes.''; PubMedEurope PMCScholia
Weimer C, Beck R, Eckert P, Reckmann I, Moelleken J, Brügger B, Wieland F.; ''Differential roles of ArfGAP1, ArfGAP2, and ArfGAP3 in COPI trafficking.''; PubMedEurope PMCScholia
Donaldson JG, Kahn RA, Lippincott-Schwartz J, Klausner RD.; ''Binding of ARF and beta-COP to Golgi membranes: possible regulation by a trimeric G protein.''; PubMedEurope PMCScholia
Schuiki I, Volchuk A.; ''Diverse roles for the p24 family of proteins in eukaryotic cells.''; PubMedEurope PMCScholia
Zhao L, Helms JB, Brunner J, Wieland FT.; ''GTP-dependent binding of ADP-ribosylation factor to coatomer in close proximity to the binding site for dilysine retrieval motifs and p23.''; PubMedEurope PMCScholia
Aguilera-Romero A, Kaminska J, Spang A, Riezman H, Muñiz M.; ''The yeast p24 complex is required for the formation of COPI retrograde transport vesicles from the Golgi apparatus.''; PubMedEurope PMCScholia
Volchuk A, Ravazzola M, Perrelet A, Eng WS, Di Liberto M, Varlamov O, Fukasawa M, Engel T, Söllner TH, Rothman JE, Orci L.; ''Countercurrent distribution of two distinct SNARE complexes mediating transport within the Golgi stack.''; PubMedEurope PMCScholia
Nagahama M, Orci L, Ravazzola M, Amherdt M, Lacomis L, Tempst P, Rothman JE, Söllner TH.; ''A v-SNARE implicated in intra-Golgi transport.''; PubMedEurope PMCScholia
Spang A.; ''Retrograde traffic from the Golgi to the endoplasmic reticulum.''; PubMedEurope PMCScholia
Appenzeller-Herzog C, Hauri HP.; ''The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function.''; PubMedEurope PMCScholia
Bonnon C, Wendeler MW, Paccaud JP, Hauri HP.; ''Selective export of human GPI-anchored proteins from the endoplasmic reticulum.''; PubMedEurope PMCScholia
Yu X, Breitman M, Goldberg J.; ''A structure-based mechanism for Arf1-dependent recruitment of coatomer to membranes.''; PubMedEurope PMCScholia
Moyer BD, Allan BB, Balch WE.; ''Rab1 interaction with a GM130 effector complex regulates COPII vesicle cis--Golgi tethering.''; PubMedEurope PMCScholia
Kliouchnikov L, Bigay J, Mesmin B, Parnis A, Rawet M, Goldfeder N, Antonny B, Cassel D.; ''Discrete determinants in ArfGAP2/3 conferring Golgi localization and regulation by the COPI coat.''; PubMedEurope PMCScholia
Chun J, Shapovalova Z, Dejgaard SY, Presley JF, Melançon P.; ''Characterization of class I and II ADP-ribosylation factors (Arfs) in live cells: GDP-bound class II Arfs associate with the ER-Golgi intermediate compartment independently of GBF1.''; PubMedEurope PMCScholia
Orci L, Stamnes M, Ravazzola M, Amherdt M, Perrelet A, Söllner TH, Rothman JE.; ''Bidirectional transport by distinct populations of COPI-coated vesicles.''; PubMedEurope PMCScholia
Zink S, Wenzel D, Wurm CA, Schmitt HD.; ''A link between ER tethering and COP-I vesicle uncoating.''; PubMedEurope PMCScholia
Stephens DJ, Lin-Marq N, Pagano A, Pepperkok R, Paccaud JP.; ''COPI-coated ER-to-Golgi transport complexes segregate from COPII in close proximity to ER exit sites.''; PubMedEurope PMCScholia
Presley JF, Cole NB, Schroer TA, Hirschberg K, Zaal KJ, Lippincott-Schwartz J.; ''ER-to-Golgi transport visualized in living cells.''; PubMedEurope PMCScholia
Mesmin B, Drin G, Levi S, Rawet M, Cassel D, Bigay J, Antonny B.; ''Two lipid-packing sensor motifs contribute to the sensitivity of ArfGAP1 to membrane curvature.''; PubMedEurope PMCScholia
Goldberg J.; ''Decoding of sorting signals by coatomer through a GTPase switch in the COPI coat complex.''; PubMedEurope PMCScholia
Buechling T, Chaudhary V, Spirohn K, Weiss M, Boutros M.; ''p24 proteins are required for secretion of Wnt ligands.''; PubMedEurope PMCScholia
Lord C, Ferro-Novick S, Miller EA.; ''The highly conserved COPII coat complex sorts cargo from the endoplasmic reticulum and targets it to the golgi.''; PubMedEurope PMCScholia
Moelleken J, Malsam J, Betts MJ, Movafeghi A, Reckmann I, Meissner I, Hellwig A, Russell RB, Russell RB, Söllner T, Brügger B, Wieland FT.; ''Differential localization of coatomer complex isoforms within the Golgi apparatus.''; PubMedEurope PMCScholia
Gommel DU, Memon AR, Heiss A, Lottspeich F, Pfannstiel J, Lechner J, Reinhard C, Helms JB, Nickel W, Wieland FT.; ''Recruitment to Golgi membranes of ADP-ribosylation factor 1 is mediated by the cytoplasmic domain of p23.''; PubMedEurope PMCScholia
Zhao C, Smith EC, Whiteheart SW.; ''Requirements for the catalytic cycle of the N-ethylmaleimide-Sensitive Factor (NSF).''; PubMedEurope PMCScholia
Kawamoto K, Yoshida Y, Tamaki H, Torii S, Shinotsuka C, Yamashina S, Nakayama K.; ''GBF1, a guanine nucleotide exchange factor for ADP-ribosylation factors, is localized to the cis-Golgi and involved in membrane association of the COPI coat.''; PubMedEurope PMCScholia
Serafini T, Orci L, Amherdt M, Brunner M, Kahn RA, Rothman JE.; ''ADP-ribosylation factor is a subunit of the coat of Golgi-derived COP-coated vesicles: a novel role for a GTP-binding protein.''; PubMedEurope PMCScholia
Holleran EA, Tokito MK, Karki S, Holzbaur EL.; ''Centractin (ARP1) associates with spectrin revealing a potential mechanism to link dynactin to intracellular organelles.''; PubMedEurope PMCScholia
Majoul I, Straub M, Hell SW, Duden R, Söling HD.; ''KDEL-cargo regulates interactions between proteins involved in COPI vesicle traffic: measurements in living cells using FRET.''; PubMedEurope PMCScholia
Holleran EA, Ligon LA, Tokito M, Stankewich MC, Morrow JS, Holzbaur EL.; ''beta III spectrin binds to the Arp1 subunit of dynactin.''; PubMedEurope PMCScholia
Linstedt AD, Hauri HP.; ''Giantin, a novel conserved Golgi membrane protein containing a cytoplasmic domain of at least 350 kDa.''; PubMedEurope PMCScholia
Bremser M, Nickel W, Schweikert M, Ravazzola M, Amherdt M, Hughes CA, Söllner TH, Rothman JE, Wieland FT.; ''Coupling of coat assembly and vesicle budding to packaging of putative cargo receptors.''; PubMedEurope PMCScholia
Beck R, Rawet M, Wieland FT, Cassel D.; ''The COPI system: molecular mechanisms and function.''; PubMedEurope PMCScholia
Hara-Kuge S, Kuge O, Orci L, Amherdt M, Ravazzola M, Wieland FT, Rothman JE.; ''En bloc incorporation of coatomer subunits during the assembly of COP-coated vesicles.''; PubMedEurope PMCScholia
Liu X, Zhang C, Xing G, Chen Q, He F.; ''Functional characterization of novel human ARFGAP3.''; PubMedEurope PMCScholia
Whiteheart SW, Matveeva EA.; ''Multiple binding proteins suggest diverse functions for the N-ethylmaleimide sensitive factor.''; PubMedEurope PMCScholia
Spectrin assembles into heterodimers of alpha and beta spectrin, these then associate in a head to tail tetramer arrangement, the beta chains binding an actin filaments at either end of the tetramer. The actin filaments act as nodes for the attachment of several (5 or 6) spectrin tetramers, allowing the formation of a lattice of pentagonal or hexagonal spectrin structures.
In its GTP-bound active state, RAB1 recruits the ARF GEF GBF1 to the ERGIC (Monetta et al, 2007). GBF1 is the only ARF activator required for the formation of COPI coats, and it therefore has roles in the anterograde ERGIC-to-cis-Golgi pathway as well as in COPI-mediated retrograde transport within the Golgi and back to the ERGIC and ER (Kawamoto et al, 2002; Szul et al, 2005; Zhao et al, 2006; Szul et al, 2007; reviewed in Szul and Sztul, 2011). GBF1 activates ARF4 which is concentrated at the ERGIC compartment, but also ARF1 and ARF5 which have more generalized localization within the secretory pathway (Volpicelli-Daley et al, 2005; Chun et al, 2008; reviewed in D'Souza-Schorey and Chavrier, 2006). GBF1 also interacts with the USO1 homodimer, a long coiled-coil tethering factor (Garcia-Mata and Sztul, 2003).
GBF1 recruits inactive ARF:GDP complexes to the ERGIC (Monetta et al, 2007). There are 5 known ADP-ribosylation factor proteins (ARFs) in the human cell. Class I members ARF1 and ARF 3 are expressed at high levels and broadly distributed through the secretory system, while Class II members ARF4 and ARF5 are expressed at lower levels, with ARF4 showing the most specific localization to the ERGIC compartment. ARF6, the single Class III ARF, appears to function more specifically in endocytosis and actin dynamics (Chun et al, 2008; reviewed in D'Souza-Schorey and Chavrier, 2006; Szul and Sztul, 2011). There is conflicting evidence regarding what ARF(s) is required at the ERGIC membrane. GBF1 has been shown to activate ARF1, 4, and 5, but not ARF3, while single and pairwise knockdown of ARF1, 3, 4 and 5 suggests that although no single ARF is responsible for any given step in the secretory pathway, ARF1 and ARF3 contribute most specifically to the ERGIC-Golgi step (Manolea et al, 2010; Volpicelli-Daley et al, 2005). Recruitment of ARF at may also be facilitated by interaction with p24 family members (Gommel et al, 2001; reviewed in Schuiki and Volchuk, 2012).
GBF1 facilitates the exchange of GDP for GTP, activating ARF (Niu et al, 2005; Szul et al, 2005; Szul et al, 2007; Kawamoto et al, 2002; reviewed in Szul and Sztul, 2011).
Activation of ARF is tightly linked to the recruitment of the COPI coat (Donaldson et al, 1991; Serafini et al, 1991; Donaldson et el, 1992; Palmer et al, 1993; reveiwed in Szul and Sztul, 2011). Studies in yeast and in mammalian cells support a direct interaction between the GTPase and components of the COPI coat; recruitment may also be facilitated by interactions with p24 family members (Zhao et al, 1997; Zhao et al, 1999; Zhao et al, 2006; Eugster et al, 2000; Aguillera-Ramiero et al, 2008; Sun et al, 2007; Yu et al, 2012; Harter and Wieland, 1998; Bethune et al, 2006; reviewed in Popoff et al, 2011). The COPI coat consists of 7 subunits arranged in 2 subcomplexes. The inner coat is made up of a tetrameric complex consisting of the beta, gamma, zeta and delta COPI subunits, while the outer coat is a trimer consisting of the alpha, beta prime and epsilon subunits (Eugster et al, 2000; Waters et al, 1991). Both of the zeta and gamma subunits have 2 isoforms with different subcellular locations, suggesting that different COPI coats may mediate different steps of the secretory pathway (Moelleken et al, 2007). Unlike the case for COPII or clathrin coats, all components of the COPI coat are recruited simultaneously as a preformed heptameric complex (Hara-Kuge et al, 1994)
Binding and polymerization of the coatomer (the COPI coat) is coordinated with the incorporation of cargo proteins and Golgi-targeting snares, as well as with recruitment of ARFGAP proteins (Letourneur et al, 1994; Nagahama et al,1996; Bremser et al, 1999). Typical model cargo for COPI-mediated trafficking includes the viral glycoprotein VSV-G and proinsulin as well as the KDEL receptors, which bind and recycle ER-resident proteins and which themselves must be returned to post-ER compartments (Cosson and Letourner, 1994; Ben-Tekaya et al, 2005; Majoul et al, 2001; Orci et al, 1997, Bremser et al, 1999; Presley et al, 1997; reviewed in Beck et al, 2009). Other protein components of the COPI vesicle include the p24 family of proteins, which serve diverse roles in the early secretory pathway (reviewed in Schuiki and Volchuk, 2012). Oligomeric p24 proteins interact with ADP-bound ARF and components of the COPI coat, contributing to coatomer recruitment and oligomerization (Gommel et al, 2001; Majoul et al, 2001; Bethune et al, 2006; Harter and Wieland, 1998; Langer et al, 2008; Reinhard et al, 1999). The p24 proteins also act as cargo receptors for various proteins destined for packaging in COPI vesicles; these include GPI-anchored transmembrane proteins, WNT ligands and some G-protein coupled receptors (Takida et al, 2008; Bonnon et al, 2010; Luo et al, 2011; Beuchling et al, 2011; Wang and Kazanietz, 2002; reviewed in Schuiki and Volchuk, 2012). Finally, the p24 proteins contribute to COPI coat disassembly by restricting ARF GTPase activity until cargo has been loaded (Goldberg, 2000; Lanoix et al, 2001). ARFGAPs are recruited to the budding vesicle through direct interaction with active ARF, the cytoplasmic tails of cargo proteins and with components of the COPI coat (Goldberg, 2000; Majoul et al, 2001; Aoe et al, 1997; Kliouchnikov et al, 2009; Luo et al, 2009). Stimulation of ARF GTPase activity is coordinated with cargo recruitment to ensure that only cargo-loaded vesicles are produced (Goldberg, 2000; Luo et al, 2009). Mammalian cells have 3 ARFGAPs that appear to be involved in COPI-mediated traffic, ARFGAP1,2 and 3 (Frigerio et al, 2007; Liu et al, 2001; Kahn et al, 2008). ARFGAP1 has a ALPS domain that recognizes membrane curvature and that is required for the GTPase stimulating activity of the protein, suggesting a mechanism for coordinating ARF1-mediated GTP hydrolysis with vesicle formation (Bigay et al, 2003; Mesmin et al, 2007). ARFGAP 2 and 3 do not contain this motif, and their activity is dependent upon interaction with coatomer (Weimar et al 2008; Kliouchnikov et al, 2009; Luo et al, 2009). Finally, there is evidence that components of the ankyin/spectrin skeleton may be incorporated in the nascent COPI vesicle, acting as a bridge between cargo proteins and the dynein-dynactin complex required for their transport to the Golgi (Devarajan et al, 1997; Godi et al, 1998; Holleran et al, 1996; Holleran et al, 2001).
The ARFGAP proteins stimulates ARF GTPase activity, promoting the release of the nascent COPI vesicle from the membrane and release of ARF:ADP (Tanigawa et al, 1993; reviewed in Beck et al, 2009; East and Kahn, 2011). Although this reaction shows their dissociation, it is not clear whether ARFGAPs persist on the COPI vesicle after GTP hydrolysis, nor is it known when GBF is released from the nascent COPI vesicle.
Unlike COPII-mediated traffic from the ER, COPI traffic to the Golgi is microtubule- and dynein-dependent (Scales et al, 1997; Presley et al, 1997; Ben-Tekaya et al, 2005). Recruitment of the dynein:dynactin complex may in turn rely on interaction with the ankyrin-spectrin network, which may contact integral membrane cargo proteins as they are incorporated into nascent COPI vesicles (Devarajan et al, 1997; Godi et al, 1998; Holleran et al, 1996; Holleran et al, 2001). Although not depicted in this reaction, dynein-dependent vesicle transport is energy dependent.
Vesicles tethering at the cis-Golgi is mediated both by long coiled-coil tethers and by large multisubunit complexes. Vesicle-bound USO1 homodimers associate with the Golgi localized GOLGA2:GORASP1 complex and with the Golgi-localized octameric COG tethering complex (Allan et al, 2000; Moyer et al, 2001; Weide et al, 2001; Nakamura et al, 1997; Seeman et al, 2000; Sohda et al, 2007). GOLGB1 is another Golgi localized tether that may facilitate vesicle tethering at the cis-Golgi, although it is also implicated in intra-Golgi retrograde trafficking (Linstedt and Hauri, 1993; Sonnichsen et al, 1998; Alvarez et al, 2001; Beard et al, 2005; reviewed in Appenzeller-Herzog et al, 2006). In addition to binding to USO1, the COG complex also interacts with components of the COPI coat, as well as with SNARE proteins and the TMEM115 protein (Suvorova et al, 2002; Zolov et al, 2005; Shestakova et al, 2007; Ong et al, 2014; reviewed in Willet et al, 2013).
The mechanisms of COPI vesicle uncoating are not well established (reviewed in Szul and Sztul, 2011). Coat dissociation may be promoted by changes in protein-protein interactions upon vesicle tethering, as has been suggested for retrograde COPI-traffic to the ER (Zink et al, 2009). After uncoating and membrane fusion, the SNARE complex exists as a four-helix bundle that must be "unzipped" (dissociated) by NSF for reuse, an energetically costly event (reviewed in Hong and Lev, 2014; Sudhof and Rothman, 2009).
Membrane fusion is mediated by the zippering of a four membered anti-parallel helix bundle formed by the v-SNARE and the three t-SNARES. t-SNARE complexes that are found at the cis-Golgi include STX5:GOSR1:GOSR2, STX5:GOSR1:BET1 and STX5:GOSR1:BET1L among others (Xu et al, 2002; Zhang et al 1997; Volchuk et al, 2004; reviewed in Willet et al, 2014; Szul and Sztul, 2011)
After membrane fusion, the cis-SNARE complex is dissociated in an ATP-dependent fashion by the AAA protein NSF in conjunction with SNAP proteins (Mayer et al, 1996; Sollner et al, 1993; reviewed in Jahn and Scheller, 2006; Sudhof and Rothman, 2009).
NSF-dependent hydrolysis of ATP is required to disassociate the cis-SNARE complex, releasing the SNAREs for further rounds of membrane fusion (Mayer et al, 1996; Muller et al, 1999; Muller et al, 2002; Otto et al, 1997; Whiteheart et al, 2004; Yu et al, 1999; Zhao et al, 2012; Shah et al, 2015; reviewed in Sudhof and Rothman, 2009).
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Typical model cargo for COPI-mediated trafficking includes the viral glycoprotein VSV-G and proinsulin as well as the KDEL receptors, which bind and recycle ER-resident proteins and which themselves must be returned to post-ER compartments (Cosson and Letourner, 1994; Ben-Tekaya et al, 2005; Majoul et al, 2001; Orci et al, 1997, Bremser et al, 1999; Presley et al, 1997; reviewed in Beck et al, 2009).
Other protein components of the COPI vesicle include the p24 family of proteins, which serve diverse roles in the early secretory pathway (reviewed in Schuiki and Volchuk, 2012). Oligomeric p24 proteins interact with ADP-bound ARF and components of the COPI coat, contributing to coatomer recruitment and oligomerization (Gommel et al, 2001; Majoul et al, 2001; Bethune et al, 2006; Harter and Wieland, 1998; Langer et al, 2008; Reinhard et al, 1999). The p24 proteins also act as cargo receptors for various proteins destined for packaging in COPI vesicles; these include GPI-anchored transmembrane proteins, WNT ligands and some G-protein coupled receptors (Takida et al, 2008; Bonnon et al, 2010; Luo et al, 2011; Beuchling et al, 2011; Wang and Kazanietz, 2002; reviewed in Schuiki and Volchuk, 2012). Finally, the p24 proteins contribute to COPI coat disassembly by restricting ARF GTPase activity until cargo has been loaded (Goldberg, 2000; Lanoix et al, 2001).
ARFGAPs are recruited to the budding vesicle through direct interaction with active ARF, the cytoplasmic tails of cargo proteins and with components of the COPI coat (Goldberg, 2000; Majoul et al, 2001; Aoe et al, 1997; Kliouchnikov et al, 2009; Luo et al, 2009). Stimulation of ARF GTPase activity is coordinated with cargo recruitment to ensure that only cargo-loaded vesicles are produced (Goldberg, 2000; Luo et al, 2009).
Mammalian cells have 3 ARFGAPs that appear to be involved in COPI-mediated traffic, ARFGAP1,2 and 3 (Frigerio et al, 2007; Liu et al, 2001; Kahn et al, 2008). ARFGAP1 has a ALPS domain that recognizes membrane curvature and that is required for the GTPase stimulating activity of the protein, suggesting a mechanism for coordinating ARF1-mediated GTP hydrolysis with vesicle formation (Bigay et al, 2003; Mesmin et al, 2007). ARFGAP 2 and 3 do not contain this motif, and their activity is dependent upon interaction with coatomer (Weimar et al 2008; Kliouchnikov et al, 2009; Luo et al, 2009).
Finally, there is evidence that components of the ankyin/spectrin skeleton may be incorporated in the nascent COPI vesicle, acting as a bridge between cargo proteins and the dynein-dynactin complex required for their transport to the Golgi (Devarajan et al, 1997; Godi et al, 1998; Holleran et al, 1996; Holleran et al, 2001).