Journal
JOURNAL OF HEPATOLOGY
Volume 59, Issue 1, Pages 52-58Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2013.03.019
Keywords
Hepatitis C virus; Interferon; NS4B; STING/MITA; TBK-1
Categories
Funding
- Chinese National Science and Technology Major Project [2012ZX10002007-003]
- Chinese MOST 973 Program [2009CB522501, 2009CB522504]
- CAS/SAFEA International Partnership Program for Creative Research Teams
- Institut Pasteur International Network [ACIP-AP20]
- Grants-in-Aid for Scientific Research [25293110] Funding Source: KAKEN
Ask authors/readers for more resources
Background & Aims: Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. Methods: We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism. Results: We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP. induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. Conclusions: In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available