ARFGAP1 promotes AP-2-dependent endocytosis

Bai, Ming; Gad, Helge; Turacchio, Gabriele; Cocucci, Emanuele; Yang, Jia‐Shu; Li, Jian Jian; Beznoussenko, Galina V.; Nie, Zhongzhen; Luo, Rubai; Fu, Lianwu; Collawn, James F.; Kirchhausen, Tomas; Luini, Alberto; Hsu, Victor

doi:10.1038/ncb2221

Cited by 36 publications

(48 citation statements)

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“…Another class of proteins that has been shown to bind clathrin in animal systems is the ADP ribosylation factor GTPaseactivating protein (ARF GAP) family, whose members induce the hydrolysis of GTP bound to ARF and are essential factors to couple vesicle formation with cargo loading (Tanabe et al, 2005;Natsume et al, 2006;Spang et al, 2010;Bai et al, 2011). However, there are no prior reports of plant ARF GAPs binding to clathrin or having a role in vacuolar trafficking.…”

Section: Introductionmentioning

confidence: 91%

“…Most studies have centered on the prototypical mammalian ArfGAP1, which is involved in COPI vesicle formation. Knowledge about ARF GAPs involved in CCV formation is much more limited, although the basic mechanisms may well be the same (reviewed in Kon et al, 2011), and a recent study found an unexpected involvement of ArfGAP1 also in CCV formation (Bai et al, 2011). The initial hypothesis that ArfGAP1 triggers vesicle coat disassembly by the ARF-GTP to ARF-GDP conversion has been revisited over the last 10 years, and several, more refined models for ARF GAP function have been proposed (reviewed in Nie and Randazzo, 2006;Spang, et al, 2010).…”

Section: Discussion the Molecular Mode Of Action Of Mtv1 And Nev/agd5mentioning

confidence: 99%

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MTV1 and MTV4 Encode Plant-Specific ENTH and ARF GAP Proteins That Mediate Clathrin-Dependent Trafficking of Vacuolar Cargo from the Trans-Golgi Network

et al. 2013

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Many soluble proteins transit through the trans-Golgi network (TGN) and the prevacuolar compartment (PVC) en route to the vacuole, but our mechanistic understanding of this vectorial trafficking step in plants is limited. In particular, it is unknown whether clathrin-coated vesicles (CCVs) participate in this transport step. Through a screen for modified transport to the vacuole (mtv) mutants that secrete the vacuolar protein VAC2, we identified MTV1, which encodes an EPSIN N-TERMINAL HOMOLOGY protein, and MTV4, which encodes the ADP ribosylation factor GTPase-activating protein NEVERSHED/AGD5. MTV1 and NEV/AGD5 have overlapping expression patterns and interact genetically to transport vacuolar cargo and promote plant growth, but they have no apparent roles in protein secretion or endocytosis. MTV1 and NEV/AGD5 colocalize with clathrin at the TGN and are incorporated into CCVs. Importantly, mtv1 nev/agd5 double mutants show altered subcellular distribution of CCV cargo exported from the TGN. Moreover, MTV1 binds clathrin in vitro, and NEV/AGD5 associates in vivo with clathrin, directly linking these proteins to CCV formation. These results indicate that MTV1 and NEV/AGD5 are key effectors for CCV-mediated trafficking of vacuolar proteins from the TGN to the PVC in plants.

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Section: Introductionmentioning

confidence: 91%

Section: Discussion the Molecular Mode Of Action Of Mtv1 And Nev/agd5mentioning

confidence: 99%

MTV1 and MTV4 Encode Plant-Specific ENTH and ARF GAP Proteins That Mediate Clathrin-Dependent Trafficking of Vacuolar Cargo from the Trans-Golgi Network

et al. 2013

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“…A positive role for SMAP1 is compatible with the function of other ARF GAP proteins whose knockdown impairs vesicle transport. For example, targeting of ARF GAP1 impaired transferrin endocytosis (30), suggesting an ARF GAP1-dependent but SMAP1/2-independent route of transferrin endocytosis. In any case, our results support a positive role of SMAP1 in vesicle formation and may contribute to the discussion on the putative terminator versus effector functions of ARF GAPs (31,32).…”

Section: Figurementioning

confidence: 99%

Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia

et al. 2013

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The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking between subcellular compartments and is triggered by the ARF family of small GTPases. We previously identified SMAP1 as an ARF6 GTPase-activating protein that functions in clathrin-dependent endocytosis. Because abnormalities in clathrin-dependent trafficking are often associated with oncogenesis, we targeted Smap1 in mice to examine its physiological and pathological significance. Smap1-deficent mice exhibited healthy growth, but their erythroblasts showed enhanced transferrin endocytosis. In mast cells cultured in SCF, Smap1 deficiency did not affect the internalization of c-KIT but impaired the sorting of internalized c-KIT from multivesicular bodies to lysosomes, resulting in intracellular accumulation of undegraded c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, approximately 50% of aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are hematological abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, to our knowledge these results provide the first evidence in a mouse model that the deregulation of clathrin-dependent membrane trafficking may be involved in the development of MDS and subsequent AML. IntroductionIntracellular and extracellular homeostasis is maintained by a vesicle transport system that mediates the trafficking of membrane proteins to appropriate organelles. Clathrin-coated vesicles are formed at donor membrane sites in a highly ordered manner, and a number of molecules are involved in this process. Among them, small GTPases of the ARF family play a central role in vesicle formation. An ARF molecule cycles between two conformations, an active GTP-bound form and an inactive GDP-bound form. This cycling is mediated by a guanine nucleotide exchange factor that replaces GDP with GTP and a GTPase-activating protein (GAP) that hydrolyzes GTP to GDP and converts ARF into its inactive form. There are 6 ARFs (ARF1-ARF6) and several ARF-related proteins in mammals (1, 2). ARF6 is an isoform that localizes mainly to the plasma membrane and functions in the endocytosis and recycling of vesicles as well as in actin rearrangement and lipid metabolism (3,4).We previously demonstrated that small ARF GAP1 (referred to as SMAP1) is a regulator of clathrin-dependent endocytosis, based on a series of observations (5, 6). First, SMAP1 exhibits GAP activity against ARF6, as assessed by an in vitro GAP assay. Second, SMAP1 localizes to juxta-plasma membrane regions in which ARF6 also exists. Third, SMAP1 binds to the clathrin heavy chain directly via its clathrin-binding box. Fourth, overexpression of SMAP1 abrogates clathrin-dependent internalization of the transferrin receptor and E-cadherin.

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“…Immunoprecipitation experiments and GST pulldown experiments were performed as previously described (19,20).…”

Section: Methodsmentioning

confidence: 99%

Hepatitis C Virus NS5A Hijacks ARFGAP1 To Maintain a Phosphatidylinositol 4-Phosphate-Enriched Microenvironment

Yang

et al. 2014

J Virol

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Phosphatidylinositol 4-phosphate (PI4P) is well known to be upregulated during hepatitis C virus (HCV) replication. The role of PI4 kinases in HCV has been extensively investigated. Whether the PI4P phosphatase Sac1 is altered by HCV remains unclear. Here, we identified ARFGAP1 to be a novel host factor for HCV replication. We further show that Sac1 interacts with ARFGAP1 and inhibits HCV replication. The elevation of PI4P induced by HCV NS5A is abrogated when the coatomer protein I (COPI) pathway is inhibited. We also found an interaction between NS5A and ARFGAP1. Furthermore, we identified a conserved cluster of positively charged amino acids in NS5A critical for interaction between NS5A and ARFGAP1, induction of PI4P, and HCV replication. Our data demonstrate that ARFGAP1 is a host factor for HCV RNA replication. ARFGAP1 is hijacked by HCV NS5A to remove COPI cargo Sac1 from the site of HCV replication to maintain high levels of PI4P. Our findings provide an additional mechanism by which HCV enhances formation of a PI4P-rich environment. IMPORTANCEPI4P is enriched in the replication area of HCV; however, whether PI4P phosphatase Sac1 is subverted by HCV is not established. The detailed mechanism of how COPI contributes to viral replication remains unknown, though COPI components were hijacked by HCV. We demonstrate that ARFGAP1 is hijacked by HCV NS5A to remove COPI cargo Sac1 from the HCV replication area to maintain high-level PI4P generated by NS5A. Furthermore, we identify a conserved cluster of positively charged amino acids in NS5A, which are critical for interaction between NS5A and ARFGAP1, induction of PI4P, and HCV replication. This study will shed mechanistic insight on how other RNA viruses hijack COPI and Sac1. H epatitis C virus (HCV) is a major cause of chronic liver disease, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma, infecting about 170 million people worldwide (1). Treatment of patients with a combination of pegylated interferon and ribavirin produces only a sustained virological response in about 50% of patients and often produces serious side effects. Direct translation of the HCV genome gives rise to a polyprotein precursor, which can be further processed by host and viral proteases into structural proteins and nonstructural proteins. Nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B are necessary and sufficient for RNA replication (2).A hallmark of HCV replication is the formation of a membranous web which is induced mainly by NS4B (3). Recent studies have shown that NS5A plays an essential role for maintaining membranous web integrity by activating PI4 kinase type III alpha (PI4KA) to elevate phosphatidylinositol 4-phosphate (PI4P) during HCV infection (4-8). Whether the host transport pathway is involved in the PI4P generation by NS5A is unknown.Sac1 is the key phosphatase that dephosphorylates PI4P (9). Previous work has suggested that Sac1 is a coatomer protein I (COPI) cargo which contains a KXKXX motif (10). Key factors in the COPI pathway, in...

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ARFGAP1 promotes AP-2-dependent endocytosis

Cited by 36 publications

References 58 publications

MTV1 and MTV4 Encode Plant-Specific ENTH and ARF GAP Proteins That Mediate Clathrin-Dependent Trafficking of Vacuolar Cargo from the Trans-Golgi Network

MTV1 and MTV4 Encode Plant-Specific ENTH and ARF GAP Proteins That Mediate Clathrin-Dependent Trafficking of Vacuolar Cargo from the Trans-Golgi Network

Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia

Hepatitis C Virus NS5A Hijacks ARFGAP1 To Maintain a Phosphatidylinositol 4-Phosphate-Enriched Microenvironment

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