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

  1. Jung-Hyun Choi
  2. Xu Zhang
  3. Christine Zhang
  4. David L. Dai
  5. Jun Luo
  6. Reese Ladak
  7. Qian Li
  8. Shane Wiebe
  9. Alex C.H. Liu
  10. Xiaozhuo Ran
  11. Jiaqi Yang
  12. Parisa Naeli
  13. Aitor Garzia
  14. Lele Zhou
  15. Niaz Mahmood
  16. Qiyun Deng
  17. Mohamed Elaish
  18. Rongtuan Lin
  19. Tom Hobman
  20. Jerry Pelletier
  21. Tommy Alain
  22. Silvia Vidal
  23. Thomas Duchaine
  24. Mohammad T. Mazhab-Jafari
  25. Xiaojuan Mao
  26. Seyed Mehdi Jafarnejad
  27. Nahum Sonenberg
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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 novel mechanism by which the SARS-CoV-2 virus co-opts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded Non-Structural 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, leading to reduced viral infection. Our findings reveal a new target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

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