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

doi:10.1016/j.celrep.2020.108342

Type-IInterferon-Inducible SERTAD3 Inhibits Influenza A Virus Replication by Blocking the Assembly of Viral RNA Polymerase Complex

Cell Rep. 2020 Nov 3;33(5):108342. doi: 10.1016/j.celrep.2020.108342.

Authors

Nina Sun¹, Chunfeng Li², Xiao-Feng Li³, Yong-Qiang Deng³, Tao Jiang³, Na-Na Zhang³, Shulong Zu¹, Rong-Rong Zhang³, Lili Li⁴, Xiang Chen³, Ping Liu⁵, Sarah Gold⁶, Ning Lu⁷, Peishuang Du⁷, Jingfeng Wang⁸, Cheng-Feng Qin⁹, Genhong Cheng¹⁰

Affiliations

¹ 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.
² Institute for Immunity, Transplantation and Infection, Department of Pathology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
³ Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
⁴ 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.
⁵ 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.
⁶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China.
⁸ 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. Electronic address: jingfengwang@g.ucla.edu.
⁹ Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China. Electronic address: qincf@bmi.ac.cn.
¹⁰ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: gcheng@mednet.ucla.edu.

PMID: 33147462
DOI: 10.1016/j.celrep.2020.108342

Abstract

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.

Keywords: IAV; IFN-stimulated genes; RNA-dependent RNA polymerase; SERTAD3; type I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Dogs
HEK293 Cells
Humans
Influenza A virus / drug effects
Influenza A virus / enzymology*
Influenza A virus / physiology*
Interferon Type I / metabolism*
Madin Darby Canine Kidney Cells
Mice, Inbred C57BL
Mice, Knockout
Peptides / pharmacology
Protein Binding / drug effects
Protein Subunits / metabolism
Trans-Activators / metabolism*
Viral Replicase Complex Proteins / metabolism*
Virus Replication / drug effects
Virus Replication / physiology*

Substances

Interferon Type I
Peptides
Protein Subunits
SERTAD3 protein, human
Sertad3 protein, mouse
Trans-Activators
Viral Replicase Complex Proteins