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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling

Yi Zheng, Meng-Wei Zhuang, Lulu Han, Jing Zhang, Mei-Ling Nan, Chengjiang Gao, View ORCID ProfilePei-Hui Wang
doi: https://doi.org/10.1101/2020.07.26.222026
Yi Zheng
1Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Meng-Wei Zhuang
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Lulu Han
1Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Jing Zhang
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Mei-Ling Nan
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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Chengjiang Gao
1Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
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  • For correspondence: cgao@sdu.edu.cn pei-hui.wang@sdu.edu.cn pei-hui.wang@connect.hku.hk
Pei-Hui Wang
2Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
3Suzhou Research Institute, Shandong University, Shandong University, Suzhou, Jiangsu 215123, China
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  • ORCID record for Pei-Hui Wang
  • For correspondence: cgao@sdu.edu.cn pei-hui.wang@sdu.edu.cn pei-hui.wang@connect.hku.hk
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Abstract

The coronavirus disease 2019 (COVID-19) caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 27, 2020.
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling
Yi Zheng, Meng-Wei Zhuang, Lulu Han, Jing Zhang, Mei-Ling Nan, Chengjiang Gao, Pei-Hui Wang
bioRxiv 2020.07.26.222026; doi: https://doi.org/10.1101/2020.07.26.222026
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling
Yi Zheng, Meng-Wei Zhuang, Lulu Han, Jing Zhang, Mei-Ling Nan, Chengjiang Gao, Pei-Hui Wang
bioRxiv 2020.07.26.222026; doi: https://doi.org/10.1101/2020.07.26.222026

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