TM6SF2 Promotes Lipidation and Secretion of Hepatitis C Virus in Infected Hepatocytes

Gastroenterology
Audrey BoyerT Jake Liang

Abstract

Hepatitis C virus (HCV) co-opts the very-low-density lipoprotein pathway for morphogenesis, maturation, and secretion, and circulates as lipoviroparticles (LVPs). We investigated the functions and underlying mechanisms of the lipid-associated TM6SF2 protein in modulating LVP formation and the HCV life cycle. We knocked down or overexpressed TM6SF2 in hepatic cells and examined HCV infection, measuring viral RNA and protein levels and infectious LVP titers. The density of secreted LVPs was evaluated by iodixanol gradient assay. We measured levels and patterns of TM6SF2 in liver biopsies from 73 patients with chronic hepatitis C, livers of HCV-infected humanized Alb-uPA/SCID/beige mice, and HCV-infected Huh7.5.1 cells. TM6SF2 knockdown in hepatocytes reduced viral RNA and infectious viral particle secretion without affecting HCV genome replication, translation, or assembly. Overexpression of TM6SF2 reduced intracellular levels of HCV RNA and infectious LVPs, and conversely increased their levels in the culture supernatants. In HCV-infected cells, TM6SF2 overexpression resulted in production of more infectious LVPs in the lower-density fractions of supernatant. HCV infection increased TM6SF2 expression in cultured cells, humanized...Continue Reading

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Citations

Jan 23, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Bernhard ScheinerMattias Mandorfer
Jun 17, 2020·PLoS Pathogens·Gabrielle VieyresThomas Pietschmann
Aug 10, 2021·World Journal of Gastroenterology : WJG·Hui-Chun LiShih-Yen Lo

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