Hepatitis C virus-induced degradation of cell death-inducing DFFA-like effector B leads to hepatic lipid dysregulation

Lee, E. M., Alsagheir, A., Wu, X., Hammack, C., McLauchlan, J. , Watanabe, N., Wakita, T., Kneteman, N. M., Douglas, D. N. and Tang, H. (2016) Hepatitis C virus-induced degradation of cell death-inducing DFFA-like effector B leads to hepatic lipid dysregulation. Journal of Virology, 90(8), pp. 4174-4185. (doi: 10.1128/JVI.02891-15) (PMID:26865724)

Abstract

Chronically infected hepatitis C individuals commonly exhibit hepatic intracellular lipid accumulation, termed steatosis. Hepatitis C virus (HCV) infection perturbs host lipid metabolism through both cellular and viral-induced mechanisms, with the viral core protein playing an important role in steatosis development. We have recently identified a liver protein, the cell death-inducing DFFA-like effector B (CIDEB), as a HCV entry host dependence factor that is downregulated by HCV infection in a cell culture model. Here, we investigate the biological significance and molecular mechanism of this downregulation. HCV infection in a mouse model downregulated CIDEB in the liver tissue, and knockout of CIDEB gene in a hepatoma cell line results in multiple aspects of lipid dysregulation that can contribute to hepatic steatosis, including reduced triglyceride secretion, lower lipidation of very low density lipoproteins, and increased lipid droplet (LD) stability. The potential link between CIDEB downregulation and steatosis is further supported by the requirement of HCV core and its LD localization for CIDEB downregulation, which utilize a proteolytic cleavage event that is independent of the cellular proteasomal degradation of CIDEB. IMPORTANCE: Our data demonstrate that HCV infection of human hepatocytes in vitro and in vivo results in CIDEB downregulation via a proteolytic cleavage event. Reduction of CIDEB protein levels by HCV or gene-editing in turn leads to multiple aspects of lipid dysregulation including LD stabilization. As such, CIDEB downregulation may contribute to HCV-induced hepatic steatosis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McLauchlan, Professor John
• Authors: Lee, E. M., Alsagheir, A., Wu, X., Hammack, C., McLauchlan, J., Watanabe, N., Wakita, T., Kneteman, N. M., Douglas, D. N., and Tang, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Journal of Virology
• Publisher: American Society for Microbiology
• ISSN: 0022-538X
• ISSN (Online): 1098-5514
• Copyright Holders: Copyright © 2016 American Society for Microbiology
• First Published: First published in Journal of Virology 90(8):4174-4185
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.