SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Author:

Xu Zhang12,Choi Jung-Hyun12,Dai David L.3,Luo Jun12,Ladak Reese Jalal12,Li Qian4,Wang Yimeng5,Zhang Christine6,Wiebe Shane12,Liu Alex C. H.3,Ran Xiaozhuo3,Yang Jiaqi3,Naeli Parisa7,Garzia Aitor8,Zhou Lele12,Mahmood Niaz12,Deng Qiyun12,Elaish Mohamed91011ORCID,Lin Rongtuan5ORCID,Mahal Lara K.9ORCID,Hobman Tom C.10ORCID,Pelletier Jerry12,Alain Tommy12,Vidal Silvia M.13,Duchaine Thomas12,Mazhab-Jafari Mohammad T.3,Mao Xiaojuan6,Jafarnejad Seyed Mehdi7ORCID,Sonenberg Nahum12ORCID

Affiliation:

1. Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, H3A 1A3, Canada

2. Department of Biochemistry, McGill University, Montreal, QC, H3A 1A3, Canada

3. Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 2C1, Canada

4. Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, QC, H4A 3J1, Canada

5. Lady Davis Institute, Department of Medicine, McGill University, Montreal, QC, H3T 1E2, Canada

6. Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada

7. Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, Northern Ireland, BT9 7AE, United Kingdom

8. Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY 10065

9. Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada

10. Department of Cell Biology, University of Alberta, Edmonton, AB T6G 2H7, Canada

11. Poultry Diseases Department, Faculty of Veterinary Medicine, Cairo University, Giza, 12613 Egypt

12. Children’s Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, K1H 5B2, Canada

13. Department of Human Genetics, McGill University, Montreal, QC, H3G 0B1 Canada

Abstract

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Funder

Gouvernement du Canada | Canadian Institutes of Health Research

Terry Fox Research Institute

UKRI | Biotechnology and Biological Sciences Research Council

National Research Foundation of Korea

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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