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

Zhang Xu; Jung-Hyun Choi; David L Dai; Jun Luo; Reese Jalal Ladak; Qian Li; Yimeng Wang; Christine Zhang; Shane Wiebe; Alex C H Liu; Xiaozhuo Ran; Jiaqi Yang; Parisa Naeli; Aitor Garzia; Lele Zhou; Niaz Mahmood; Qiyun Deng; Mohamed Elaish; Rongtuan Lin; Lara K Mahal; Tom C Hobman; Jerry Pelletier; Tommy Alain; Silvia M Vidal; Thomas Duchaine; Mohammad T Mazhab-Jafari; Xiaojuan Mao; Seyed Mehdi Jafarnejad; Nahum Sonenberg

doi:10.1073/pnas.2204539119

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

Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2204539119. doi: 10.1073/pnas.2204539119. Epub 2022 Jul 25.

Authors

Zhang Xu^{1

2}, Jung-Hyun Choi^{1

2}, David L Dai³, Jun Luo^{1

2}, Reese Jalal Ladak^{1

2}, Qian Li⁴, Yimeng Wang⁵, Christine Zhang⁶, Shane Wiebe^{1

2}, Alex C H Liu³, Xiaozhuo Ran³, Jiaqi Yang³, Parisa Naeli⁷, Aitor Garzia⁸, Lele Zhou^{1

2}, Niaz Mahmood^{1

2}, Qiyun Deng^{1

2}, Mohamed Elaish^{9

10

11}, Rongtuan Lin⁵, Lara K Mahal⁹, Tom C Hobman¹⁰, Jerry Pelletier^{1

2}, Tommy Alain¹², Silvia M Vidal¹³, Thomas Duchaine^{1

2}, Mohammad T Mazhab-Jafari³, Xiaojuan Mao⁶, Seyed Mehdi Jafarnejad⁷, Nahum Sonenberg^{1

2}

Affiliations

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.

Keywords: 4EHP; GIGYF2; NSP2; SARS-CoV-2; mRNA translation.

Publication types

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

MeSH terms

COVID-19* / genetics
Carrier Proteins* / metabolism
Cell Line
Eukaryotic Initiation Factor-4E / metabolism
Humans
Immunity, Innate
Interferon Type I* / metabolism
Protein Biosynthesis
RNA, Messenger / genetics
SARS-CoV-2
Viral Nonstructural Proteins* / metabolism
Virus Replication

Substances

Carrier Proteins
EIF4E2 protein, human
Eukaryotic Initiation Factor-4E
GIGYF2 protein, human
Interferon Type I
RNA, Messenger
Viral Nonstructural Proteins
nsp2 protein, SARS-CoV-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding