title: Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core.
abstract: The triglyceride-synthesizing enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) plays a critical role in hepatitis C virus (HCV) infection by recruiting the HCV capsid protein core onto the surface of cellular lipid droplets (LDs). Here we find a new interaction between the non-structural protein NS5A and DGAT1 and show that the trafficking of NS5A to LDs depends on DGAT1 activity. DGAT1 forms a complex with NS5A and core and facilitates the interaction between both viral proteins. A catalytically inactive mutant of DGAT1 (H426A) blocks the localization of NS5A, but not core, to LDs in a dominant-negative manner and impairs the release of infectious viral particles, underscoring the importance of DGAT1-mediated translocation of NS5A to LDs in viral particle production. We propose a model whereby DGAT1 serves as a cellular hub for HCV core and NS5A proteins, guiding both onto the surface of the same subset of LDs, those generated by DGAT1. These results highlight the critical role of DGAT1 as a host factor for HCV infection and as a potential drug target for antiviral therapy.
authors: Gladstone Institute of Virology and Immunology, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
authors: Gregory
authors: G
authors: Camus
authors: Gladstone Institute of Virology and Immunology, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; UCSF Liver Center, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
authors: Eva
authors: E
authors: Herker
authors: Gladstone Institute of Virology and Immunology, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
authors: Ankit A
authors: AA
authors: Modi
authors: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158.
authors: Joel T
authors: JT
authors: Haas
authors: Gladstone Institute of Virology and Immunology, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
authors: Holly R
authors: HR
authors: Ramage
authors: UCSF Liver Center, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158; Department of Medicine, University of California, San Francisco, California 94158; Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158.
authors: Robert V
authors: RV
authors: Farese
authors: Gladstone Institute of Virology and Immunology, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; UCSF Liver Center, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; Department of Medicine, University of California, San Francisco, California 94158. Electronic address: mott@gladstone.ucsf.edu.
authors: Melanie
authors: M
authors: Ott
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002213:Capsid / Q000737:chemistry; D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase / Q000737:chemistry* / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D005799:Genes, Dominant; D057809:HEK293 Cells; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014280:Triglycerides / Q000737:chemistry / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000502:physiology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D051048:Diacylglycerol O-Acyltransferase; D008055:Lipids; D014280:Triglycerides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase