Regulation of Hepatitis C Virus Infection by Cellular Retinoic Acid Binding Proteins through the Modulation of Lipid Droplet Abundance

Author:

Bang Bo-Ram1ORCID,Li Meng2,Tsai Kuen-Nan3,Aoyagi Haruyo4,Lee Shin-Ae3,Machida Keigo35,Aizaki Hideki4,Jung Jae U.3ORCID,Ou Jing-Hsiung James3,Saito Takeshi13675ORCID

Affiliation:

1. Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

2. Bioinformatics Service, Norris Medical Library, University of Southern California, Los Angeles, California, USA

3. Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

4. Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

5. Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

6. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

7. USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Abstract

ATRA, a biologically active metabolite of vitamin A, exerts pleiotropic biological effects, including the activation of both innate and adaptive immunity, thereby serving as a potent antimicrobial compound against numerous viral pathogens. Despite the enrichment of hepatocytes with vitamin A, HCV still establishes an efficient viral life cycle. Here, we discovered that the hepatocellular response to ATRA creates either a proviral or an antiviral environment depending on its engagement with CRABP1 or -2, respectively. CRABP1 supports the robust replication of HCV, while CRABP2 potently inhibits the efficiency of viral replication. Our biochemical, genetic, and microscopic analyses reveal that the pro- and antiviral effects of CRABPs are mediated by modulation of LD abundance, where HCV establishes the platform for viral replication and assembly on the LD-associated ER membrane. This study uncovered a cell-intrinsic mechanism by which HCV exploits the proviral function of CRABP1 to establish an efficient viral life cycle.

Funder

PhoenixBio

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

CRDF Global

HHS | NIH | National Institute on Alcohol Abuse and Alcoholism

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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