title: Identification of class II ADP-ribosylation factors as cellular factors required for hepatitis C virus replication.
abstract: GBF1 is a host factor required for hepatitis C virus (HCV) replication. GBF1 functions as a guanine nucleotide exchange factor for G-proteins of the Arf family, which regulate membrane dynamics in the early secretory pathway and the metabolism of cytoplasmic lipid droplets. Here we established that the Arf-guanine nucleotide exchange factor activity of GBF1 is critical for its function in HCV replication, indicating that it promotes viral replication by activating one or more Arf family members. Arf involvement was confirmed with the use of two dominant negative Arf1 mutants. However, siRNA-mediated depletion of Arf1, Arf3 (class I Arfs), Arf4 or Arf5 (class II Arfs), which potentially interact with GBF1, did not significantly inhibit HCV infection. In contrast, the simultaneous depletion of both Arf4 and Arf5, but not of any other Arf pair, imposed a significant inhibition of HCV infection. Interestingly, the simultaneous depletion of both Arf4 and Arf5 had no impact on the activity of the secretory pathway and induced a compaction of the Golgi and an accumulation of lipid droplets. A similar phenotype of lipid droplet accumulation was also observed when GBF1 was inhibited by brefeldin A. In contrast, the simultaneous depletion of both Arf1 and Arf4 resulted in secretion inhibition and Golgi scattering, two actions reminiscent of GBF1 inhibition. We conclude that GBF1 could regulate different metabolic pathways through the activation of different pairs of Arf proteins.
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Rayan
authors.initials: R
authors.lastname: Farhat
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Séron
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Ferlin
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Fénéant
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Belouzard
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.|Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Goueslain
authors.affiliation: Institut Jacques Monod, CNRS UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Jackson
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204, CIIL - Center for Infection and Immunity of Lille, Lille, France.
authors.forename: Yves
authors.identifier: 0000-0003-0788-9271
authors.initials: Y
authors.lastname: Rouillé
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D045744:Cell Line, Tumor; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000201:enzymology / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D066292:Lipid Droplets; D000072417:Protein Domains; D021381:Protein Transport; D055571:Secretory Pathway; D014779:Virus Replication
chemical_list: C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D020823:ADP-Ribosylation Factor 1