Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway

PLoS Pathogens
Yisha LiangJin Zhong

Abstract

Toll-like receptor 3 (TLR3) senses dsRNA intermediates produced during RNA virus replication to activate innate immune signaling pathways through adaptor protein TRIF. Many viruses have evolved strategies to block TLR3-mediated interferon signaling via targeting TRIF. Here we studied how hepatitis C virus (HCV) antagonizes the TLR3-mediated interferon signaling. We found that HCV-encoded NS4B protein inhibited TLR3-mediated interferon signaling by down-regulating TRIF protein level. Mechanism studies indicated that the downregulation of TRIF by NS4B was dependent on caspase8. NS4B transfection or HCV infection can activate caspase8 to promote TRIF degradation, leading to suppression of TLR3-mediated interferon signaling. Knockout of caspase8 can prevent TRIF degradation triggered by NS4B, thereby enhancing the TLR3-mediated interferon signaling activation in response to HCV infection. In conclusion, our work revealed a new mechanism for HCV to evade innate immune response by blocking the TLR3-mediated interferon signaling via NS4B-induced TRIF degradation.

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Citations

Feb 13, 2019·Journal of Medical Microbiology·Paywast J JalalAlexander W Tarr
Mar 19, 2020·Journal of Clinical Medicine·Ana Rita FerreiraDaniela Ribeiro
Jul 18, 2020·Viruses·Madeleine L Stolz, Craig McCormick
Jan 1, 2020·Journal of Cell Science·Lin LuoJennifer L Stow
Apr 12, 2020·International Journal of Molecular Sciences·Pil Soo Sung, Eui-Cheol Shin
Apr 11, 2021·European Journal of Immunology·Zhenliang HeJin Zhong
Jun 29, 2021·Applied Microbiology and Biotechnology·Pengpeng XiaGuoqiang Zhu
Aug 31, 2021·Frontiers in Immunology·Samaa T GobranNaglaa H Shoukry
Sep 15, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Marion DelphinSuzanne Faure-Dupuy

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Methods Mentioned

BETA
transfection
Assay

Software Mentioned

Image J
GraphPad Prism

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