Type-IInterferon-Inducible SERTAD3 Inhibits Influenza A Virus Replication by Blocking the Assembly of Viral RNA Polymerase Complex
Nina Sun,
Chunfeng Li,
Xiao-Feng Li,
Yong-Qiang Deng,
Tao Jiang,
Na-Na Zhang,
Shulong Zu,
Rong-Rong Zhang,
Lili Li,
Xiang Chen,
Ping Liu,
Sarah Gold,
Ning Lu,
Peishuang Du,
Jingfeng Wang,
Cheng-Feng Qin,
Genhong Cheng
Affiliations
Nina Sun
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 100101, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of System Medicine, Suzhou, Jiangsu 215123, China
Chunfeng Li
Institute for Immunity, Transplantation and Infection, Department of Pathology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
Xiao-Feng Li
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Yong-Qiang Deng
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Tao Jiang
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Na-Na Zhang
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Shulong Zu
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 100101, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of System Medicine, Suzhou, Jiangsu 215123, China
Rong-Rong Zhang
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Lili Li
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of System Medicine, Suzhou, Jiangsu 215123, China
Xiang Chen
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
Ping Liu
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 100101, China
Sarah Gold
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
Ning Lu
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
Peishuang Du
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China
Jingfeng Wang
Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Suzhou Institute of System Medicine, Suzhou, Jiangsu 215123, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Cheng-Feng Qin
Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; Corresponding author
Genhong Cheng
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Summary: Influenza A virus (IAV) infection stimulates a type I interferon (IFN-I) response in host cells that exerts antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). However, most ISGs are poorly studied for their roles in the infection of IAV. Herein, we demonstrate that SERTA domain containing 3 (SERTAD3) has a significant inhibitory effect on IAV replication in vitro. More importantly, Sertad3−/− mice develop more severe symptoms upon IAV infection. Mechanistically, we find SERTAD3 reduces IAV replication through interacting with viral polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA) to disrupt the formation of the RNA-dependent RNA polymerase (RdRp) complex. We further identify an 8-amino-acid peptide of SERTAD3 as a minimum interacting motif that can disrupt RdRp complex formation and inhibit IAV replication. Thus, our studies not only identify SERTAD3 as an antiviral ISG, but also provide the mechanism of potential application of SERTAD3-derived peptide in suppressing influenza replication.
