Journal
SCIENCE SIGNALING
Volume 8, Issue 403, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aab2159
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Funding
- National Natural Science Foundation of China [81325012]
- Ministry of Science and Technology of China [2015CB554302, 2009CB522505]
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The transcription factor nuclear factor kB (NF-kappa B) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF-kappa B essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-kappa B signaling in host cells, which promotes pathogen survival. Frequently, HCV-infected individuals develop a chronic infection, which suggests that HCV can subvert host antiviral responses. We found that HCV infection and replication inhibited the activation of NF-kappa B by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), which was mediated by the viral protein NS3 and, to a lesser extent, NS5B. NS3 directly interacted with linear ubiquitin chain assembly complex (LUBAC), competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO and the subsequent activation of NF-kappa B. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence.
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