The mammalian Golgi complex, a central hub of both anterograde and retrograde trafficking, is a ribbon of stacked cisterna with biochemically distinct compartments (reviewed in Glick and Nakano, 2009; Szul and Sztul, 2011). Anterograde cargo from the ERGIC and ER is received at the cis-Golgi, trafficked through the medial- and trans-Golgi and released through the trans-Golgi network (TGN) to the endolysosomal system and the plasma membrane. Although still under debate, current models of Golgi trafficking favour the cisternal maturation model, where anterograde cargo remain associated with their original lipid membrane during transit through the Golgi and are exposed to sequential waves of processing enzymes by the retrograde movement of Golgi resident proteins. In this way, cis-cisterna mature to medial- and trans-cisterna as the early acting Golgi enzymes are replaced by later acting ones (reviewed in Pelham, 2001; Storrie, 2005; Glick and Nakano, 2009; Szul and Sztul, 2011). More recently. a kiss-and-run (KAR) model for intra-Golgi trafficking has been proposed, which marries aspects of the cisternal maturation model with a diffusion model of transport (reviewed in Mironov et al, 2103). Like the anterograde ERGIC-to Golgi transport step, intra-Golgi trafficking between the cisterna appears to be COPI-dependent (Storrie and Nilsson, 2002; Szul and Sztul, 2011). Numerous snares and tethering complexes contribute to the targeting and fusion events that are required to maintain the specificity and directionality of these trafficking events (reviewed in Chia and Gleeson, 2014). Golgi tethers include long coiled coiled proteins like the Golgins, as well as multisubunit tethers like the COG complex. These tethers make numerous interactions with other components of the secretory system including RABs, SNAREs, motor and coat proteins as well as components of the cytoskeleton (reviewed in Munro, 2011; Willet et al, 2013). Retrograde traffic from the cis-Golgi back to the ERGIC and ER depends on both the COPI-dependent pathway, which appears to be important for recyling of KDEL receptors, and a more recently described COPI-independent pathway that relies on RAB6 (reviewed in Szul and Sztul, 2011; Heffernan and Simpson, 2014). RAB6 and RAB9 also play roles at the TGN side of the Golgi, where they are implicated in the docking of vesicles derived from the endolysosomal system and the plasma membrane (reviewed in Pfeffer, 2011)
View original pathway at:Reactome.
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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
Conibear E, Stevens TH.; ''Vps52p, Vps53p, and Vps54p form a novel multisubunit complex required for protein sorting at the yeast late Golgi.''; PubMedEurope PMCScholia
Gillingham AK, Pfeifer AC, Munro S.; ''CASP, the alternatively spliced product of the gene encoding the CCAAT-displacement protein transcription factor, is a Golgi membrane protein related to giantin.''; PubMedEurope PMCScholia
Girod A, Storrie B, Simpson JC, Johannes L, Goud B, Roberts LM, Lord JM, Nilsson T, Pepperkok R.; ''Evidence for a COP-I-independent transport route from the Golgi complex to the endoplasmic reticulum.''; PubMedEurope PMCScholia
Béthune J, Kol M, Hoffmann J, Reckmann I, Brügger B, Wieland F.; ''Coatomer, the coat protein of COPI transport vesicles, discriminates endoplasmic reticulum residents from p24 proteins.''; PubMedEurope PMCScholia
de Figueiredo P, Polizotto RS, Drecktrah D, Brown WJ.; ''Membrane tubule-mediated reassembly and maintenance of the Golgi complex is disrupted by phospholipase A2 antagonists.''; PubMedEurope PMCScholia
Tarricone C, Xiao B, Justin N, Walker PA, Rittinger K, Gamblin SJ, Smerdon SJ.; ''The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways.''; PubMedEurope PMCScholia
Bechler ME, de Figueiredo P, Brown WJ.; ''A PLA1-2 punch regulates the Golgi complex.''; 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
Yoshino A, Setty SR, Poynton C, Whiteman EL, Saint-Pol A, Burd CG, Johannes L, Holzbaur EL, Koval M, McCaffery JM, Marks MS.; ''tGolgin-1 (p230, golgin-245) modulates Shiga-toxin transport to the Golgi and Golgi motility towards the microtubule-organizing centre.''; PubMedEurope PMCScholia
Cardenas J, Rivero S, Goud B, Bornens M, Rios RM.; ''Golgi localisation of GMAP210 requires two distinct cis-membrane binding mechanisms.''; PubMedEurope PMCScholia
Barbero P, Bittova L, Pfeffer SR.; ''Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells.''; 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
Tripathi A, Ren Y, Jeffrey PD, Hughson FM.; ''Structural characterization of Tip20p and Dsl1p, subunits of the Dsl1p vesicle tethering complex.''; PubMedEurope PMCScholia
Panic B, Whyte JR, Munro S.; ''The ARF-like GTPases Arl1p and Arl3p act in a pathway that interacts with vesicle-tethering factors at the Golgi apparatus.''; PubMedEurope PMCScholia
Heffernan LF, Simpson JC.; ''The trials and tubule-ations of Rab6 involvement in Golgi-to-ER retrograde transport.''; PubMedEurope PMCScholia
Setty SR, Shin ME, Yoshino A, Marks MS, Burd CG.; ''Golgi recruitment of GRIP domain proteins by Arf-like GTPase 1 is regulated by Arf-like GTPase 3.''; PubMedEurope PMCScholia
Munro S.; ''The golgin coiled-coil proteins of the Golgi apparatus.''; 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
Laufman O, Hong W, Lev S.; ''The COG complex interacts directly with Syntaxin 6 and positively regulates endosome-to-TGN retrograde transport.''; PubMedEurope PMCScholia
Liewen H, Meinhold-Heerlein I, Oliveira V, Schwarzenbacher R, Luo G, Wadle A, Jung M, Pfreundschuh M, Stenner-Liewen F.; ''Characterization of the human GARP (Golgi associated retrograde protein) complex.''; PubMedEurope PMCScholia
Nakajima K, Hirose H, Taniguchi M, Kurashina H, Arasaki K, Nagahama M, Tani K, Yamamoto A, Tagaya M.; ''Involvement of BNIP1 in apoptosis and endoplasmic reticulum membrane fusion.''; PubMedEurope PMCScholia
Mossessova E, Gulbis JM, Goldberg J.; ''Structure of the guanine nucleotide exchange factor Sec7 domain of human arno and analysis of the interaction with ARF GTPase.''; PubMedEurope PMCScholia
Storrie B.; ''Maintenance of Golgi apparatus structure in the face of continuous protein recycling to the endoplasmic reticulum: making ends meet.''; PubMedEurope PMCScholia
Hirose H, Arasaki K, Dohmae N, Takio K, Hatsuzawa K, Nagahama M, Tani K, Yamamoto A, Tohyama M, Tagaya M.; ''Implication of ZW10 in membrane trafficking between the endoplasmic reticulum and Golgi.''; 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
Siniossoglou S, Pelham HR.; ''Vps51p links the VFT complex to the SNARE Tlg1p.''; PubMedEurope PMCScholia
Kelly EE, Giordano F, Giordano F, Horgan CP, Jollivet F, Raposo G, McCaffrey MW.; ''Rab30 is required for the morphological integrity of the Golgi apparatus.''; 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
Martin S, Driessen K, Nixon SJ, Zerial M, Parton RG.; ''Regulated localization of Rab18 to lipid droplets: effects of lipolytic stimulation and inhibition of lipid droplet catabolism.''; PubMedEurope PMCScholia
Letourneur F, Gaynor EC, Hennecke S, Démollière C, Duden R, Emr SD, Riezman H, Cosson P.; ''Coatomer is essential for retrieval of dilysine-tagged proteins to the endoplasmic reticulum.''; PubMedEurope PMCScholia
Pérez-Victoria FJ, Bonifacino JS.; ''Dual roles of the mammalian GARP complex in tethering and SNARE complex assembly at the trans-golgi network.''; PubMedEurope PMCScholia
Wu M, Lu L, Hong W, Song H.; ''Structural basis for recruitment of GRIP domain golgin-245 by small GTPase Arl1.''; 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
Zhao C, Smith EC, Whiteheart SW.; ''Requirements for the catalytic cycle of the N-ethylmaleimide-Sensitive Factor (NSF).''; PubMedEurope PMCScholia
Ben-Tekaya H, Miura K, Pepperkok R, Hauri HP.; ''Live imaging of bidirectional traffic from the ERGIC.''; PubMedEurope PMCScholia
D'Souza-Schorey C, Chavrier P.; ''ARF proteins: roles in membrane traffic and beyond.''; PubMedEurope PMCScholia
Drin G, Morello V, Casella JF, Gounon P, Antonny B.; ''Asymmetric tethering of flat and curved lipid membranes by a golgin.''; 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
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
Stauber T, Simpson JC, Pepperkok R, Vernos I.; ''A role for kinesin-2 in COPI-dependent recycling between the ER and the Golgi complex.''; PubMedEurope PMCScholia
Ferraro F, Kriston-Vizi J, Metcalf DJ, Martin-Martin B, Freeman J, Burden JJ, Westmoreland D, Dyer CE, Knight AE, Ketteler R, Cutler DF.; ''A two-tier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells.''; PubMedEurope PMCScholia
Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA.; ''Rab18 and a Rab18 GEF complex are required for normal ER structure.''; PubMedEurope PMCScholia
Storrie B, Nilsson T.; ''The Golgi apparatus: balancing new with old.''; 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
Short B, Preisinger C, Schaletzky J, Kopajtich R, Barr FA.; ''The Rab6 GTPase regulates recruitment of the dynactin complex to Golgi membranes.''; PubMedEurope PMCScholia
Liu S, Hunt L, Storrie B.; ''Rab41 is a novel regulator of Golgi apparatus organization that is needed for ER-to-Golgi trafficking and cell growth.''; PubMedEurope PMCScholia
Andag U, Neumann T, Schmitt HD.; ''The coatomer-interacting protein Dsl1p is required for Golgi-to-endoplasmic reticulum retrieval in yeast.''; PubMedEurope PMCScholia
Laufman O, Kedan A, Hong W, Lev S.; ''Direct interaction between the COG complex and the SM protein, Sly1, is required for Golgi SNARE pairing.''; 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
Goldberg J.; ''Decoding of sorting signals by coatomer through a GTPase switch in the COPI coat complex.''; PubMedEurope PMCScholia
Setty SR, Strochlic TI, Tong AH, Boone C, Burd CG.; ''Golgi targeting of ARF-like GTPase Arl3p requires its Nalpha-acetylation and the integral membrane protein Sys1p.''; PubMedEurope PMCScholia
Pulvirenti T, Giannotta M, Capestrano M, Capitani M, Pisanu A, Polishchuk RS, San Pietro E, Beznoussenko GV, Mironov AA, Turacchio G, Hsu VW, Sallese M, Luini A.; ''A traffic-activated Golgi-based signalling circuit coordinates the secretory pathway.''; PubMedEurope PMCScholia
Ganley IG, Espinosa E, Pfeffer SR.; ''A syntaxin 10-SNARE complex distinguishes two distinct transport routes from endosomes to the trans-Golgi in human cells.''; 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
McKnight NC, Jefferies HB, Alemu EA, Saunders RE, Howell M, Johansen T, Tooze SA.; ''Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC.''; 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
Siniossoglou S, Pelham HR.; ''An effector of Ypt6p binds the SNARE Tlg1p and mediates selective fusion of vesicles with late Golgi membranes.''; PubMedEurope PMCScholia
Luke MR, Houghton F, Perugini MA, Gleeson PA.; ''The trans-Golgi network GRIP-domain proteins form alpha-helical homodimers.''; PubMedEurope PMCScholia
Hsia KC, Hoelz A.; ''Crystal structure of alpha-COP in complex with epsilon-COP provides insight into the architecture of the COPI vesicular coat.''; PubMedEurope PMCScholia
Behnia R, Panic B, Whyte JR, Munro S.; ''Targeting of the Arf-like GTPase Arl3p to the Golgi requires N-terminal acetylation and the membrane protein Sys1p.''; 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
Espinosa EJ, Calero M, Sridevi K, Pfeffer SR.; ''RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport.''; PubMedEurope PMCScholia
GBF1 recruits inactive ARF:GDP complexes to the Golgi (Monetta et al, 2007). There are 5 known 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 5 are expressed at lower levels. 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). 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 no single ARF is responsible for any given step in the secretory pathway (Manolea et al, 2010; Volpicelli-Daley et al, 2005).
Activation of ARF is tightly correlated to 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 (Zhao et al, 1997; Zhao et al, 1999; Zhao et al, 2006; Eugster et al, 2000; 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).
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).
In its GTP-bound active state, RAB1 recruits the ARF GEF GBF1 to the Golgi (Monetta et al, 2007). GBF is the only ARF activator required for the formation of COPI coats, and therefore it has roles in the anterograde ERGIC-to-cis-Golgi as well as in COPI-mediated retrograd 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). GBR1 activates ARF1, 2, 3 and 5 which play overlapping roles in the secretory pathway (Volpicelli-Daley et al, 2005; Chun et al, 2008; reviewed in D'Souza-Schorey and Chavrier, 2006).
Binding and polymerization of coatomer 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 cargo for COPI-mediated retrograde traffic includes the KDEL receptors, which bind and recycle ER-resident proteins, as well as other cycling proteins such as SURF4 that interacts with p24 proteins and contributes to Golgi maintenance (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; Mitrovic et al, 2008; 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). 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, among others (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). p24 proteins also 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).
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.
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).
Retrograde COPI vesicles destined for fusion with the ER are tethered to the ER membrane by interactions with the ER t-SNARE proteins and with the CATCHR ('complexes associated with tethering containing helical rods') complex NRZ (reviewed in Szul and Sztul, 2011; Tagaya et al, 2014). The trimeric NRZ complex, known as Dsl in yeast, is composed of NBAS, RINT1 and ZW10 and is recruited to the ER through association with the ER t-SNAREs USE1L, STX18 and BNIP1 (Hirose et al, 2004; Aoki et al, 2004; Nakajima et al, 2004; Arasaki et al, 2006; Ren et al, 2009; Civril et al, 2010; reviewed in Tagaya et al, 2014). Evidence in yeast suggests components of the Dsl complex also interact with the coatomer coat; these interactions contribute to vesicle fusion both by aiding in the recruitment of the vesicle to the ER membrane and also to the depolymerization of coatomer and thus vesicle uncoating Interactions (Andag et al, 2001; Andag et al, 2003; Reilly et al, 2001; Hsia and Hoelz, 2010; Meiringer et al, 2011; Zink et al, 2009). Note that although this pathway shows COPI vesicles from the Golgi being 'received' exclusively at the ER, vesicles are also tethered and fused at the ERGIC. The SNAREs and tethering complexes that mediate this fusion are not identified.
After membrane fusion, the 4-membered cis-SNARE complex is dissociated in an ATP-dependent manner by SNAP and NSF (Mayer et al, 1996; Sollner et al, 1993; reviewed in Jahn and Scheller, 2006; Sudhof and Rothman, 2009).
COPI-mediated retrograde traffic is dependent on microtubules and the plus-end motor kinsesin. Although it is not shown in this reaction, vesicle translocation along the microtubules by kinesin depends on ATP hydrolysis (Lippincott-Scwartz et al, 1995; Stauber et al, 2006; Tomas et al, 2010)
While the details of COPI vesicle uncoating are not fully established, interactions between components of the NRZ tethering complex and coatomer may contribute to coat depolymerization and release (Zink et al, 2009; Ren et al, 2009; Tripathi et al, 2009; reviewed in Barlowe and Fink, 2013).
RAB proteins are required for the RINT-1/ZW10 and COG-dependent organization of the Golgi ribbon stack, and for the trafficking of proteins through the Golgi. Indeed, cargo traffic through the Golgi depends on the maintenance of the Golgi stacks (Hirose et al, 2004; Arasaki et al, 2006; Sun et al, 2007; reviewed in Liu and Storrie, 2015). RAB6 is the primary RAB protein involved in intra-Golgi trafficking; it also has roles in COPI-independent retrograde traffic from the Golgi to the ER. RAB6A is a widely expressed isoform, while RAB6B is restricted to neuronal tissue (Darchen and Goud, 2000). RAB6 is localized to the trans-Golgi network (TGN), and a GTP-locked constitutively active form induces concentration of Golgi enzymes into the ER (Ferrano et al, 2104; Jiang and Storrie, 2005; Martinex et al, 1997; Micaroni et al, 2013; Storrie et al, 2012; Sun et al, 2007; Young et al, 2005). Inactive RAB6:GDP is recruited to the TGN through interaction with the RIC1:RGP1 complex, which also acts as a guanine nucleotide exchange factor (GEF) for RAB6 (Pusapati et al, 2012; Siniossoglou et al, 2000; Siniossoglou et al, 2001).
The RIC1:RGP1 complex stimulates nucleotide exchange on trans-Golgi network (TGN)-localized RAB6, activating it (Pusapati et al, 2012; Siniossoglou et al 2001; Siniossoglou et al, 2000). Acitvated RAB6 nucleates a tethering complex at the TGN that is required for fusion of endosome-derived vesicles arriving at the late Golgi (Siniossoglou et al, 2001; Liewen et al, 2005; Perez-Victoria et al, 2008; Perez-Victoria et al, 2009; reviewed in Bonaficino and Hierro, 2011).
Active RAB6 contributes to the recruitment of the Golgi-associated retrograde protein (GARP) tethering complex to the TGN, where it aids in the capture of retrograde vesicles from the early endosome (Liewen et al, 2005; reviewed in Bonifacino and Hierro, 2011). Typical cargo of these vesicles includes resident TGN proteins such as TGOLN2 (also known as TGN46) and internalized Shiga toxin subunit B (STx-B) and cholera toxin (Perez-Victoria et al, 2008; Ganley et al 2008; Pusapati et al, 2012; reviewed in Pfeffer, 2011; Liu and Storrie, 2012). Two studies have identifed RAB43 and its associated GAP USP6NL as being required for the retrograde traffic of Shiga toxin, however the details of this remain to be worked out (Haas et al, 2007; Fuchs et al, 2007). The human GARP complex consists of VPS54, VPS53, VPS52 and VPS51 and has been shown to interact with GTP-bound RAB6, with the TGN SNAREs STX10 and STX16 and with a vesicle fraction containing the v-SNARE VAMP4 (Connibear et al, 2000; Liewen et al, 2005; Perez-Victoria et al, 2009; Perez-Victoria et al, 2010; Siniossoglou and Pelham, 2002; reviewed in Bonafacino and Hierro, 2011).
Like the GARP complex, the conserved oligomeric Golgi (COG) complex has also been implicated in retrograde traffic of TGOLN2 and STx-B in a STX6:STX16:VTI1A and VAMP4-dependent manner, and COG has been shown to interact directly with RAB6 (Mallard et al, 2002; Fukuda et al, 2008; Laufman et al, 2011; reviewed in Pfeffer, 2011). Despite the representation in this reaction, however, there is not yet evidence that the GARP and the COG complexes act together to facilitate the capture of a single early endosome-derived vesicle. In addition to the multisubunit tethering complexes COG and GARP, the long coiled-coil TGN-associated Golgins also contribute to tethering of vesicles derived from the early endosome (Luke et al, 2005; Derby et al, 2007; Reddy et al, 2006; Lu et al, 2004; Yoshino et al, 2005; Hayes et al, 2009; reviewed in Munro, 2011).
Octameric COG (Conserved Oligomeric Golgi) is a Golgi localized tethering complex that aids in the capture of vesicles during intra-Golgi traffic as well as the capture of retrograde vesicles from the endosome at the trans-Golgi network (Zolov and Lupashin, 2005; reviewed in Willet et al, 2013a). Consistent with this, the COG complex interacts with many of the proteins involved in vesicle targeting, including SNAREs, coat proteins and RABs, among others. At the Golgi, COG has been shown to interact with Golgi SNAREs STX6, STX6, STX16, GOSR1, GOSR2, BET1L, SNAP29, VPS45 and VTI1A, but not other Golgi SNAREs and not ERGIC-resident SNAREs (Suvorora et al, 2002; Laufman et al, 2009; Laufman et al, 2011; Laufman et al, 2013; Shestakova et al, 2007; Willet et al, 2013b). The function of each of these COG-Golgi SNARE interactions has not yet been characterized in full detail (reviewed in Willet et al, 2013a).
ARFRP1 regulates Golgi localization of ARL1, another ARF-like GTPase that itself recruits a number of Golgin-tethering factors to the TGN. Knockout strains of ARL3, the yeast homologue of ARFRP1, abrogates Golgi localization of both yeast Arl1p and the four yeast Golgin homologues, suggesting a cascade of ARL proteins is contributes to retrograde trafficking at the TGN (Setty et al, 2003; Setty et al, 2004; Behnia et al, 2004; Panic et al, 2003; reviewed in Munro, 2005; Bonafacino and Rojas, 2006). GEF and GAP proteins that regulate ARFRP1 and ARL1 activity have not yet been identified (reviewed in Munro, 2005).
Acetylation of the N-terminal methionine of ARFRP1 contributes to its interaction with the Golgi-localized membrane protein SYS1. ARFRP1 is part of an ARF cascade at the late or trans-Golgi, where it plays a role in retrograde traffic by recruiting ARL1, which in turn interacts with a number of Golgin tethering factors required for vesicle docking at the TGN (Behnia et al, 2004; Setty et al, 2004; Shin et al, 2005; reviewed in Bonifacino and Rojas, 2006; Munro, 2011).
ARFRP1 is an ARF family member GTPase that recruits ARL1 to the trans-Golgi network to play roles in retrograde trafficking of proteins from the endolysosomal system. ARFRP1 is an atypical ARF family member in that it is not myristolated, but is instead acetylated at the amino-terminal methionine by the NatC complex. Acetylation is required for the interaction of ARFRP1 with SYS1, which contributes to its targeting to its TGN (Behnia et al, 2004; Setty et al, 2004).
GTP-bound ARL1, in conjunction with RAB6 and/or RAB9, is responsible for the recruitment of the 4 trans-Golgi network associated Golgin tethering factors, GOLGA4 (also known as Golgin245), GOLGA1 (also known as Golgin97), GCC1 (also known as GCC88) and GCC2 (also known as GCC185) (Barr et al, 1999; van Valkenburgh et al, 2001; Panic et al, 2003a; Panic et al, 2003b; Wu et al, 2004; Setty et al, 2003; reviewed in Munro et al, 2011). These coiled-coil tethering factors act as homodimers and participate in the recruitment of early endolysosomal-derived vesicles to the TGN by virtue of interacting with SNAREs and RAB proteins (Luke et al 2005; Lieu et al, 2007; Burguette et al, 2008; Ganley et al, 2008; Hayes et al, 2009; reviewed in Munro et al, 2011; Pfeffer, 2011). Evidence suggests that the Golgin tethering proteins show specificity for different retrograde cargos. For instance, retrograde transport of Shiga toxin requires both GOLGA1 and GOLGA4, while GOLGA1 is dispensible for transport of mannose-6-phosphate receptors (Lu et al, 2004; Yoshino et al, 2005; Reddy et al, 2006). Similarly, GCC1, but not GCC2, is required for TGN46 retrograde transport (Lieu et al, 2007; Derby et al, 2007). A fifth TGN-localized Golgin, TMF1, may also function similarly in retrograde transport from the early endosomes as it has been shown to interact with RAB6 and to be required for retrograde transport of Shiga toxin (Fridmann-Sirkis et al, 2004; Yamane et al, 2007).
Two hybrid screening with human ARL1 as bait identified ARFIP2 as a novel ARL1:GTP-interacting partner (Van Valkenburgh et al, 2001). Interaction between ARFIP2 and ARL1 increases the amount of ARL1:GTP four-fold , although the significance of this is not clear (Van Vlakenburgh et al, 2001). ARFIP2 is also known to interact with RAC1 and to influence membrane ruffling (van Aelst et al, 1996; Tarricone et al, 2001)
Two hybrid screening with human ARL1 as bait identified SCOC as a novel ARL1:GTP-interacting partner (Van Valkenburgh et al, 2001). SCOC (short coiled coil) shares 26% identity and 51% homology with GOLGA2, binds ARL1:GTPagamma S as assessed by affinity chromatography and shows extensive colocalization wtih beta-COP and ARL1 at the Golgi, however the role of this complex is not known (Van Valkenbrugh et al, 2001). SCOC is also known to play roles in autophagy, as part of a complex with FEZ1 (McKnight et al, 2012; reviewed in Joachim et al, 2012).
ATP hydrolysis by RHOBTB is thought to promote uncoating of the late endosome-derived vesicle, releasing PLIN3/TIP47 in preparation for vesicle fusion (Espinosa et al, 2009; reviewed in Pfeffer, 2011).
After capture at the trans-Golgi network by SNAREs and tethering factors, late endosome-derived vesicles undergo membrane fusion, delivering cargo and the cis-SNARE complex to the TGN membrane. The details of this fusion event are not fully established (reviewed in Pfeffer, 2011).
RAB9 positive vesicles from the late endosomes are tethered at the trans-Golgi network (TGN) through interaction with the GARP complex, the TGN-specific Golgin GCC2 and a t-SNARE complex consisting of STX10, STX16 and VTI1A (Hayes et al, 2009; Derby et al, 2007; Reddy et al, 2006; Ganley et al, 2008; Perez-Victoria et al, 2009; Lombardi et al, 1993; Lieu et al, 2007; reviewed in Chia and Gleeson, 2014)
Retrograde traffic of mannose-6-phosphate receptors (M6PRs) from the late endosome depends on RAB9 (Lombardi et al, 1993; Riederer et al, 1994; Barbero et al, 2002; reviewed in Pfeffer, 2011). Cargo recognition at the late endosome is mediated by the RAB9-interacting protein PLIN3/TIP47, which concentrates retrograde cargo into VAMP3 RAB9 positive vesicles (Diaz et al, 1998; Carroll et al, 2001; Reddy et al, 2006; Ganley et al, 2008). RABEPK is another RAB9:GTP interacting protein that is required for retrograde transport of M6PR to the TGN (Diaz et al, 1997). At the trans-Golgi network, RAB9 and PILN3 interact with the atypical RHO GTPase related protein RHOBTB3. This interaction is required for the TGN-localization of RAB9 M6PR positive vesicles. Interaction of RAB9 with the C-terminal domain of RHOBTB3 relieves an inhibitory intramolecular interaction in RHOBTB3, allowing the N-terminal domain to achieve maximal ATP hydrolysis, which is thought to promote the release of PLIN3/TIP47 as a precursor to vesicle fusion at the TGN (Espinosa et al, 2009)
After membrane fusion, the 4-membered cis-SNARE complex is dissociated in an ATP-dependent manner by SNAP and NSF (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).
After capture at the trans-Golgi network by SNAREs and tethering factors, early endosome-derived vesicles undergo membrane fusion, delivering cargo and the cis-SNARE complex to the TGN membrane. The details of this fusion event are not fully established (reviewed in Pfeffer, 2011).
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).
After membrane fusion, the 4-membered cis-SNARE complex is dissociated in an ATP-dependent manner by SNAP and NSF (Mayer et al, 1996; Sollner et al, 1993; reviewed in Jahn and Scheller, 2006; Sudhof and Rothman, 2009).
RAB GAP USP6NL stimulates the GTPase activity of RAB43, promoting hydrolysis of GTP. Both RAB43 and USP6NL have been identifed as contributing to the retrograde transport of Shiga toxin to the Golgi, however the details of their roles remain to be elucidated (Fuchs et al, 2007; Haas et al, 2007; reviewed in Pfeffer, 2011).
RAB43 contributes to the maintenance of Golgi structure and is required for the RAB6-dependent retrograde trafficking of Shiga toxin (Fuchs et al, 2007; Haas et al, 2007). RAB43 appears to be localized to the cis side of the Golgi, so the details of how and when it affects Shiga transport remain to be clarified (Dejgaard et al, 2007). Screens of human cells identified USP6NL as a RAB43-specific GTPase activating (GAP) protein that is also implicated in Shiga trafficking (Fuchs et al, 2007; Haas et al, 2007; reviewed in Pfeffer, 2011).
Dimeric medial Golgins CUX1 (also known as CASP) and GOLGA5 (also known as Golgin-84) act in conjunction with the COG complex to tether retrograde vesicles moving within the Golgi stacks (Bascom et al, 1999; Gillingham et al, 2002; Malsam et al, 2005; Sohda et al, 2007; Sohda et al, 2010; reviewedin Szul and Sztul, 2011). Intra-Golgi vesicles are COPI-dependent, but distinct from anterograde ERGIC-to-Golgi COPI vesicles by virtue of their cargo (generally returning Golgi and ER-resident enzymes to their appropriate location in the secretory pathway, and notably lacking p24 family members; other intra Golgi cargo includes toxins such as Shiga) and the SNARE complexes they interact with (Orci et al, 1997; Lanoix et al, 2001; Malsam et al, 2005). The yeast homologue of GOLGA5, COY1, shows a genetic interaction with yeast SNARE GOS1 (human GOSR1), suggesting the intra-Golgi vesicles may rely on a GOSR1:STX5:BET1L and YKT6 SNARE complex, though the identity of the t-SNARE complex remains to be substantiated (Gillingham et al, 2002; Sohda et al, 2010). Removal of the COPI-coat is required prior to CUX1- and GOLGA5-mediated vesicle tethering (Malsam et al, 2005). Intra-Golgi transport also depends on medial RAB protein RAB33b (Jiang et al, 2005; Valsdottir et al, 2001; Pusapati et al, 2012; Starr et al, 2010). Disruption of RAB33b abolishes retrograde traffic of Shiga toxin from the trans- to cis-Golgi, and abolishes the RAB6-dependent relocalization of Golgi resident enzymes. This suggests that RAB6 and RAB33b may form sequentially acting RAB cascade that mediates intra-Golgi traffic (Starr et al, 2010; Pusapati et al, 2012). RAB33b has also been shown to interact with the RAB6 GEF RIC1:RGP1, although the significance of this interaction is unclear. In addition, RAB33b interacts by co-immunoprecipitation with endosomal proteins RABEP1 (also known as Rabaptin-5), RABGEF1 (Rabex5) and KIF20A (Rabkinesin 6); the relevance of these interactions is likewise unknown (Valsdottir et al, 2001).
Formation of the cis-SNARE complex accompanies membrane fusion, releasing the intra-Golgi cargo into the subsequent Golgi stack and allowing tethering factors to be recycled for subsequent rounds of docking (reviewed in Sudhof and Rothman 2009; Hong and Lev, 2014).
The cis-SNARE complex of STX5:PalmC-YKT6:BET1L:GOSR1 binds the NSF hexamer and alpha-SNAPs prior to the energy dependent disassembly for reuse (reviewed in Sudhof and Rothman, 2009; Hong and Lev, 2014).
NSF-mediated ATP hydrolysis promotes disassembly of the cis-SNARE complex, allowing the SNAREs to be reused in subsequent rounds of vesicle fusion (reviewed in Sudhof and Rothman, 2009; Hong and Lev, 2014).
TRIP11, also known as GMAP210, is a cis-Golgi localized coiled coil Golgin with roles in anterograde and retrograde intra-Golgi trafficking (Infante et al, 1999; Pernet-Gallay et al, 2002). TRIP11 has an N-terminal amphipathic lipid packing sensor (ALPS) domain which binds preferentially to highly curved membranes such as those on veiscles, and a GRIP-related ARF binding (GRAB) domain at its C-terminus that binds to ARF1:GTP. This asymmetric binding allows TRIP11 to tether vesicles to the Golgi membrane. This asymmetric binding of TRIP11 is maintained in part by the fact that ARFGAP1 also contains an ALPS domain and therefore stimulates the GTPase activity of any ARF1:GTP that is present in the vesicular membrane (Drin et al, 2008; Cardenas et al, 2009; Gillingham et al, 2004).
Cytohesin (CYTH) proteins 1, 2, 3 and 4 are ARF guanine nucleotide exchange factors (GEFs) for ARF1 as well as other ARFs. Recruitment to the membrane is mediated by direct interaction with ARF1:GTP as well as an interaction between the CYTH plexstrin homology (PH) domain and the lipid membrane (Chardin et al, 1996; Betz et al, 1998; Mossessova et al, 1998; Cherfils et al, 1998; Franco et al, 1998; Osagawara et al, 2000; Malaby et al, 2013).
CYTH proteins stimulate the GTPase activity of ARF1, promoting the exchange of GTP for GDP and thereby inactivating ARF1 (Franco et al, 1998; Drin et al, 2008; reviewed in Jackson and Casanova, 2000).
Medial Golgi protein RAB33B binds to both components of the RAB6 GEF complex RIC1:RGP1, and interacts with the RIC1 subunit at a site that is distinct from the RAB6-interacting site. Activated RAB33B does not change the RAB6-directed GEF activity of the RIC1:RGP1 complex, nor does it affect RAB6 binding, however overexpression of RAB33B leads to loss of RAB6 from the Golgi (Starr et al, 2010; Pusapati et al, 2012). The significance of the interaction between RAB33B and the RIC1:RGP1 complex remains to be elucidated, however it is possible that RAB6 and RAB33B form a sequential RAB cascade that contributes to COPI-dependent retrograde traffic from the trans- to medial- Golgi.
Phospholipase A (PLA2) hydrolyzes the sn-2 position of phospholipids, releasing a fatty acid and a lysophospholipid (reviewed in Six and Dennis, 2000; Kudo and Murakami, 2002). A number studies have highlighted roles for a number of PLA2s in the maintenance of Golgi function and structure (de Figueiredo et al, 1998; de Figueiredo et al, 1999). PLAs may generate phospholipid and fatty acid products that recruit effectors of Golgi function and trafficking to the membrane or that affect downstream signaling pathways. Alternately, PLA2s may contribute directly to tubule formation at the Golgi through the production of the membrane-curvature inducing lysophospholipid (reviewed in Bechler et al, 2012). PLA2s may be recruited to the Golgi in response to changes in Ca2+ and/or cargo concentration that occur as a result of secretory traffic (Micaroni et al, 2010; San Pietro et al, 2009; Pulvirenti et al, 2008).
AGPAT3 is an acyltransferase that can act on lysophosphatidylcholine to generate phosphatidylcholine (Prasad et al, 2011; Echard at al, 1998). This activity may counter the membrane tubule-inducing activity of Golgi PLA2 enzymes, thus favouring COPI-dependent vesicle formation over COPI-indendent retrograde traffic. While many lysophospholipid acyltransferases are ER-localized, AGPAT3 has been shown to also be present at the Golgi membrane, making it well situated to counter PLA2 activity during membrane tubule formation (Drecktah et al, 2003; Schmidt et al, 2009; reviewed in Ha et al, 2012; Heffernan and Simpson, 2014).
COPI-independent retrograde traffic from the Golgi to the ER depends on RAB6 and involves formation of membrane tubules instead of classical transport vesicles. COPI-dependent and COPI-independent retrograde transport appear to have distinct cargo, as anti-COPI antibodies inhibit the traffic of KDEL-containing receptors, but not that of Shiga or Shiga-like toxins, or of Golgi-resident glycosylation enzymes (White et al, 1999; Girod et al, 1999). It is not yet clear how membrane tubules formation is initiated, however cargo type and concentration, as well as lipid composition may contribute (Martinez et al, 1997; Simpson et al, 2006; de Figueiredo et al, 1998; de Figueiredo et al, 1999; reviewed in Heffernan and Simpson 2014). The presence of sn2-lysophospholipids in the Golgi membrane generates curved membranes that are thought to favour tubule formation. Lysophospholipids are generated by the activity of phopholipase A2 enzymes that hydrolyze the fatty acid at the sn-2 position; this activity is counteracted by the activity of lysophospholipid acyltransferases (LPATs). The balance of these two activities at the Golgi membrane is thought to play a role in determining whether COPI-dependent or -independent transport is favoured (de Figueiredo et al, 1998; de Figueiredo et al, 1999; Schmidt et al, 2009; reviewed in Heffernan and Simpson, 2014). Recent studies have also implicated the coiled coil homodimer Bicaudal-D (BICD) proteins in COPI-independent retrograde traffic. BICD proteins bind RAB6:GTP with their C-terminal ends and the dynein:dynactin motor complex with their N-terminal ends and in this way are thought to facilitate the recruitment of motor proteins to the RAB6 retrograde pathway (Hoogenraad et al, 2001; Matanis et al, 2002; Young et al, 2005; Januschke et al, 2007).
Retrograde tubule formation may depend on the minus-end directed dynein-dynactin motor complex, which is recruited to the Golgi through interaction with both RAB6 and BICD (Short et al, 2002; Hoogenraad et al, 2001; Matanis et al, 2002; Young et al, 2005; Januschke et al, 2007). Interaction of dynein:dynactin with RAB6:GTP activates the motor protein by displacing the PAFAH1B1 protein, which otherwise keeps the motor "idling" (Yamada et al, 2013; reviewed in Heffernan and Simpson, 2014).
The RAB6 pathway moves select retrograde cargo from the Golgi to the ER in a motor-dependent manner, although the precise details of this translocation remain to be worked out (Girod et al, 1999; White et al, 1999; reviewed in Heffernan and Simpson, 2014). Active RAB18 at the ER membrane may contribute to targeting and fusion of COPI-independent retrograde carriers through interaction with ER-localized tethering factors (Dejgaard et al, 2008; Gerondopoulos et al, 2014; Gillingham et al, 2014)
Large scale screens have identified numerous RAB proteins that interact with components of the COG complex (Fukuda et al, 2008; Miller et al, 2013; reviewed in Willet et al, 2013). Although RAB proteins are known to play key roles in trafficking and Golgi structure and function, the significance of some of these interactions is not yet clear (Kelly et al, 2012; Liu et al, 2013; reviewed in Liu and Storrie, 2015).
RAB18 is a highly conserved RAB GTPase with roles in Golgi to ER trafficking, lipid droplet formation and the regulation of secretory granules and peroxisomes (Dejgaard et al, 2008; Gerondopoulos et al, 2014; Martin et al, 2005; Ozeki et al, 2005; Vazquez-Martinez et al, 2007; Gronemeyer et al, 2013). RAB18 is recruited to the ER membrane by the RAB18 GEF complex RAB3GAP1:RAB3GAP2, a complex that was initially identified and characterized for its GAP activity towards RAB3 (Gerondopoulos et al, 2013; Fukui et al, 1997; Nagano et al, 1998).
The RAB3GAP1:RAB3GAP2 complex promotes nucleotide exchange of RAB18 at the ER membrane, activating it (Gerondopoulos et al, 2014). How active RAB18 contributes to COPI-independent retrograde Golgi-to-ER traffic remains to be worked out, however a role in tubule tethering is postulated based on the interaction of RAB18 with components of the ER localized NRZ tethering factor (Dejgaard et al, 2008; Gerondopoulos et al, 2014; Gillingham et al, 2014).
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complex:CUX1 dimer:GOLGA5
dimer:STX5:PalmC-YKT6:BET1L:GOSR1:intra-Golgi retrograde cargoendosome-to-TGN
cargoendosome-to-TGN
cargocargo:GOLGA5
dimer:GOSR1COG-interacting
RABsAnnotated Interactions
complex:CUX1 dimer:GOLGA5
dimer:STX5:PalmC-YKT6:BET1L:GOSR1:intra-Golgi retrograde cargocomplex:CUX1 dimer:GOLGA5
dimer:STX5:PalmC-YKT6:BET1L:GOSR1:intra-Golgi retrograde cargoTypical cargo for COPI-mediated retrograde traffic includes the KDEL receptors, which bind and recycle ER-resident proteins, as well as other cycling proteins such as SURF4 that interacts with p24 proteins and contributes to Golgi maintenance (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; Mitrovic et al, 2008; 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). 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, among others (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). p24 proteins also 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).
The human GARP complex consists of VPS54, VPS53, VPS52 and VPS51 and has been shown to interact with GTP-bound RAB6, with the TGN SNAREs STX10 and STX16 and with a vesicle fraction containing the v-SNARE VAMP4 (Connibear et al, 2000; Liewen et al, 2005; Perez-Victoria et al, 2009; Perez-Victoria et al, 2010; Siniossoglou and Pelham, 2002; reviewed in Bonafacino and Hierro, 2011).
Like the GARP complex, the conserved oligomeric Golgi (COG) complex has also been implicated in retrograde traffic of TGOLN2 and STx-B in a STX6:STX16:VTI1A and VAMP4-dependent manner, and COG has been shown to interact directly with RAB6 (Mallard et al, 2002; Fukuda et al, 2008; Laufman et al, 2011; reviewed in Pfeffer, 2011). Despite the representation in this reaction, however, there is not yet evidence that the GARP and the COG complexes act together to facilitate the capture of a single early endosome-derived vesicle.
In addition to the multisubunit tethering complexes COG and GARP, the long coiled-coil TGN-associated Golgins also contribute to tethering of vesicles derived from the early endosome (Luke et al, 2005; Derby et al, 2007; Reddy et al, 2006; Lu et al, 2004; Yoshino et al, 2005; Hayes et al, 2009; reviewed in Munro, 2011).
endosome-to-TGN
cargoendosome-to-TGN
cargocargo:GOLGA5
dimer:GOSR1COG-interacting
RABs