title: ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production.
abstract: Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Vieyres
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Welsch
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Gerold
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Gentzsch
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Kahl
authors.affiliation: German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany.|ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Florian W R
authors.initials: FW
authors.lastname: Vondran
authors.affiliation: Institute for Bioinformatics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.|German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Braunschweig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D015153:Blotting, Western; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000378:metabolism / Q000503:physiopathology; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism / Q000503:physiopathology; D018613:Microscopy, Confocal; D009135:Muscular Diseases / Q000378:metabolism / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D019065:Virus Assembly / Q000502:physiology*
chemical_list: D014280:Triglycerides; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human