Hepatitis C virus NS4B blocks the interaction of STING and TBK1 to evade host innate immunity

Qiang Ding, Xuezhi Cao, Jie Lu, Bing Huang, Yong Jun Liu, Nobuyuki Kato, Hong Bing Shu, Jin Zhong

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)52-58
Number of pages7
JournalJournal of Hepatology
Issue number1
Publication statusPublished - Jul 2013


  • Interferon
  • Keywords Hepatitis C virus
  • NS4B
  • TBK-1

ASJC Scopus subject areas

  • Hepatology


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