title: The hepatitis C virus protein NS3 suppresses TNF-α-stimulated activation of NF-κB by targeting LUBAC.
abstract: The transcription factor nuclear factor κB (NF-κB) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF-κB essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-κB 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-κB by the inflammatory cytokine tumor necrosis factor-α (TNF-α), 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-κB. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence.
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Jizheng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. hydeng@moon.ibp.ac.cn gcheng@mednet.ucla.edu.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China. hydeng@moon.ibp.ac.cn gcheng@mednet.ucla.edu.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Deng
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases