Identification of class II ADP-ribosylation factors as cellular factors required for hepatitis C virus replication

Farhat, Rayan; Séron, Karin; Ferlin, Juliette; Fénéant, Lucie; Belouzard, Sandrine; Goueslain, Lucie; Jackson, Catherine; Dubuisson, Jean; Rouillé, Yves

doi:10.1111/cmi.12572

Cited by 29 publications

(35 citation statements)

References 61 publications

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“…The Arf4 antibody also produced punctate labeling in the cytoplasm, but identical staining was observed in Arf4 -/- cells suggesting that it represents nonspecific staining (Fig 2C, 2F and 2H). These results indicate that the primary localization of Arf4 in ciliated cells is in the cis-medial Golgi rather than trans Golgi or cilium, a conclusion consistent with localization of GFP-tagged Arf4 [29]. …”

Section: Resultssupporting

confidence: 57%

Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration

et al. 2017

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Arf4 is proposed to be a critical regulator of membrane protein trafficking in early secretory pathway. More recently, Arf4 was also implicated in regulating ciliary trafficking, however, this has not been comprehensively tested in vivo. To directly address Arf4’s role in ciliary transport, we deleted Arf4 specifically in either rod photoreceptor cells, kidney, or globally during the early postnatal period. Arf4 deletion in photoreceptors did not cause protein mislocalization or retinal degeneration, as expected if Arf4 played a role in protein transport to the ciliary outer segment. Likewise, Arf4 deletion in kidney did not cause cystic disease, as expected if Arf4 were involved in general ciliary trafficking. In contrast, global Arf4 deletion in the early postnatal period resulted in growth restriction, severe pancreatic degeneration and early death. These findings are consistent with Arf4 playing a critical role in endomembrane trafficking, particularly in the pancreas, but not in ciliary function.

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Section: Resultssupporting

confidence: 57%

Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration

et al. 2017

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“…During poliovirus infection, GBF1 is also recruited early to RNA replication sites. However, in this case, the colocalization is still visible at later time points (56), in line with the existence of differences of GBF1 involvement in HCV and poliovirus replication (33,57).…”

Section: Discussionsupporting

confidence: 81%

“…However, the involvement of this kinase during HCV genome replication is still controversial (28)(29)(30)(31)(32). Moreover, we recently demonstrated that the function of GBF1 during HCV genome replication is not mediated by Arf1 and is distinct from its regulatory functions with respect to the cellular secretory pathway and the morphology of the Golgi complex (33). GBF1 function in HCV replication is mediated by the pair Arf4 and Arf5, whereas its function in the regulation of the secretory pathway is mediated by the pair Arf1 and Arf4 (33,34).…”

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confidence: 99%

“…Moreover, we recently demonstrated that the function of GBF1 during HCV genome replication is not mediated by Arf1 and is distinct from its regulatory functions with respect to the cellular secretory pathway and the morphology of the Golgi complex (33). GBF1 function in HCV replication is mediated by the pair Arf4 and Arf5, whereas its function in the regulation of the secretory pathway is mediated by the pair Arf1 and Arf4 (33,34). The involvement of class II Arfs in viral replication appears to be conserved for some, but not all, RNA viruses (35).…”

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confidence: 99%

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Functional and Physical Interaction between the Arf Activator GBF1 and Hepatitis C Virus NS3 Protein

Lebsir

Goueslain

Farhat

et al. 2019

J Virol

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GBF1 has emerged as a host factor required for the genome replication of RNA viruses of different families. During the hepatitis C virus (HCV) life cycle, GBF1 performs a critical function at the onset of genome replication but is dispensable when the replication is established. To better understand how GBF1 regulates HCV infection, we have looked for interactions between GBF1 and HCV proteins. NS3 was found to interact with GBF1 in yeast two-hybrid, coimmunoprecipitation, and proximity ligation assays and to interfere with GBF1 function and alter GBF1 intracellular localization in cells expressing NS3. The interaction was mapped to the Sec7 domain of GBF1 and the protease domain of NS3. A reverse yeast two-hybrid screen to identify mutations altering NS3-GBF1 interaction yielded an NS3 mutant (N77D, Con1 strain) that is nonreplicative despite conserved protease activity and does not interact with GBF1. The mutated residue is exposed at the surface of NS3, suggesting it is part of the domain of NS3 that interacts with GBF1. The corresponding mutation in strain JFH-1 (S77D) produces a similar phenotype. Our results provide evidence for an interaction between NS3 and GBF1 and suggest that an alteration of this interaction is detrimental to HCV genome replication. IMPORTANCE Single-stranded, positive-sense RNA viruses rely to a significant extent on host factors to achieve the replication of their genome. GBF1 is such a cellular protein that is required for the replication of several RNA viruses, but its mechanism of action during viral infections is not yet defined. In this study, we investigated potential interactions that GBF1 might engage in with proteins of HCV, a GBF1dependent virus. We found that GBF1 interacts with NS3, a nonstructural protein involved in HCV genome replication, and our results suggest that this interaction is important for GBF1 function during HCV replication. Interestingly, GBF1 interaction with HCV appears different from its interaction with enteroviruses, another group of GBF1-dependent RNA viruses, in keeping with the fact that HCV and enteroviruses use different functions of GBF1. H epatitis C virus (HCV) is a small, enveloped, single-stranded, positive-sense RNA virus that infects human hepatocytes and causes persistent infection in most HCV patients. HCV replicates its genome in the cytoplasm of the host cell. Its RNAdependent RNA polymerase and other nonstructural proteins implicated in genome replication are found in association with rearranged cellular membranes, which have been named the membranous web (1). The membranous web is composed of single membrane and double membrane vesicles (2, 3) originating from the endoplasmic reticulum (ER) membrane. Two viral proteins, NS4B and NS5A, appear to play a major role in the induction of membrane rearrangements (3, 4). The protease and helicase NS3-4A and the RNA-dependent RNA polymerase NS5B are also included in HCV replication complexes, in addition to NS4B and NS5A. Cell host factors from the ER such as VAP-A (5) and phosphatidylinosi...

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“…Enteroviruses, which belong to the family Picornaviridae, rely on both protein and lipid components of the host secretory pathway to provide the structural foundation of their replication complexes (17). Recently, the guanine nucleotide exchange factor GBF1 and its effector ADP ribosylation factor 1 (Arf1), known to regulate Golgi membrane trafficking and organelle structure in the secretory pathway, were identified as host factors required for efficient HCV replication (18)(19)(20)(21). This requirement suggests that Golgi components have a role in HCV replication.…”

Section: Significancementioning

confidence: 99%

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

Hansen

Johnsen

Stiberg

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

114

127

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Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.HCV | Golgi fragmentation | autophagy | IRGM | membranous web H epatitis C virus (HCV) is a positive-sense RNA virus in the family Flaviviridae that is a major cause of chronic liver disease. All positive-strand RNA viruses studied until now, including HCV, replicate their genomes in association with cellular membrane rearrangements. In this process, viruses remodel intracellular membranes [e.g., of mitochondria, endoplasmic reticulum (ER), and plasma membrane] to generate membrane structures such as single-or double-membrane vesicles that contribute to viral replication complexes (VRCs). HCV replication takes place at a unique subcellular compartment, the membranous web (MW), which has been proposed to be derived from the ER (1, 2). The HCV MW has a complex morphology consisting of clusters of single-, double-, and multimembrane vesicles and probably includes autophagosomes and lipid droplets (1, 3, 4). Recent findings reveal that the MW is produced by distinct HCV nonstructural (NS) proteins acting through sequential interaction with several host factors, such as the virus-targeted phosphatidylinositol-4 kinase III α (PI4KIIIα) (2, 3), but the full spectrum of host components and precise membrane composition that supports HCV replication are not fully defined.Autophagy is an evolutionarily conserved cellular mechanism that involves intracellular membrane trafficking and degradation to maintain cell homeostasis. Viruses, including HCV, have been reported to exploit autophagy for replication purposes (4-6), but the mechanism by which this exploitation occurs is largely unknown. De novo synthesis of autophagosomes is a complex process that involves the formation of a phagophore membrane and its elongation. Initiation of autophagy is regulated by the mammalian target of rapamycin complex 1 (mTORC1), which neg...

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Identification of class II ADP-ribosylation factors as cellular factors required for hepatitis C virus replication

Cited by 29 publications

References 61 publications

Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration

Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration

Functional and Physical Interaction between the Arf Activator GBF1 and Hepatitis C Virus NS3 Protein

Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M

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