title: Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.|Hepacivirus and Innate Immunity, Institut Pasteur, 75015 Paris, France.
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Hansen
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
authors.forename: Ingvild B
authors.initials: IB
authors.lastname: Johnsen
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Stiberg
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sherstova
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Centre of Molecular Inflammation Research (CEMIR), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
authors.forename: Gabriel Mary
authors.initials: GM
authors.lastname: Richard
authors.affiliation: Centre of Molecular Inflammation Research (CEMIR), Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Kandasamy
authors.affiliation: Hepacivirus and Innate Immunity, Institut Pasteur, 75015 Paris, France.
authors.forename: Eliane F
authors.initials: EF
authors.lastname: Meurs
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway; marit.w.anthonsen@ntnu.no.
authors.forename: Marit W
authors.initials: MW
authors.lastname: Anthonsen
mesh_terms: D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000821:virology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D014779:Virus Replication / Q000502:physiology*
chemical_list: C120445:GBF1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; D019204:GTP-Binding Proteins; C513539:IRGM protein, human
keywords: Golgi fragmentation; HCV; IRGM; autophagy; membranous web