title: TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein.
abstract: Tripartite motif 14 (TRIM14) was reported to function as a mitochondrial signaling adaptor in mediating innate immune responses. However, the involvement of TRIM14 in host defense against viral infection and molecular mechanisms remain unclear. Here, we demonstrated that enforced expression of TRIM14 could potently inhibit the infection and replication of HCV in hepatocytes, whereas TRIM14 knockout cells became more susceptible to HCV infection. Interestingly, further experiments revealed that such anti-HCV activity was independent of activating the NF-κB or interferon pathways but required the C-terminal SPRY domain of no signaling capacity. In searching for mechanisms how TRIM14 exerts its antiviral function we found that TRIM14 interacted with HCV encoded non-structural protein NS5A and could strongly induce its degradation dependent on the NS5A1 subdomain. Interestingly extensive domain mapping analyses revealed that NS5A degradation was mediated by the highly conserved SPRY domain of TRIM14, which might involve the K48 ubiquitination pathway. Collectively, our work uncovered a new mechanism responsible for host defense against HCV infection, and could potentially aid the development of novel anti-HCV therapeutics.
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.|Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.
authors: Shanshan
authors: S
authors: Wang
authors: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors: Yongzhi
authors: Y
authors: Chen
authors: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.
authors: Chunfeng
authors: C
authors: Li
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
authors: Yaoxing
authors: Y
authors: Wu
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
authors: Lei
authors: L
authors: Guo
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
authors: Changwei
authors: C
authors: Peng
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
authors: Yueping
authors: Y
authors: Huang
authors: Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.|CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China.|Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
authors: Genhong
authors: G
authors: Cheng
authors: The Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.|Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.
authors: F Xiao-Feng
authors: FX
authors: Qin
mesh_terms: D000071197:B30.2-SPRY Domain / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D055786:Gene Knockout Techniques; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics* / Q000472:pathogenicity; D006526:Hepatitis C / Q000235:genetics* / Q000821:virology; D022781:Hepatocytes; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D059748:Proteolysis; D000070584:Tripartite Motif Proteins; D054875:Ubiquitination; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000070584:Tripartite Motif Proteins; D017361:Viral Nonstructural Proteins; C481145:TRIM14 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase