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

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2022-08, Vol.119 (32), p.e2204539119-e2204539119
Main Authors: Xu, Zhang, Choi, Jung-Hyun, Dai, David L., Luo, Jun, Ladak, Reese Jalal, Li, Qian, Wang, Yimeng, Zhang, Christine, Wiebe, Shane, Liu, Alex C. H., Ran, Xiaozhuo, Yang, Jiaqi, Naeli, Parisa, Garzia, Aitor, Zhou, Lele, Mahmood, Niaz, Deng, Qiyun, Elaish, Mohamed, Lin, Rongtuan, Mahal, Lara K., Hobman, Tom C., Pelletier, Jerry, Alain, Tommy, Vidal, Silvia M., Duchaine, Thomas, Mazhab-Jafari, Mohammad T., Mao, Xiaojuan, Jafarnejad, Seyed Mehdi, Sonenberg, Nahum
Format: Article
Language:English
Subjects:
Biological Sciences
Cap-binding protein
COVID-19
Cytokines
Depletion
Immune response
Immune system
Immunostimulation
Innate immunity
Interferon
mRNA
Proteins
RNA viruses
Severe acute respiratory syndrome coronavirus 2
Translation
Viral diseases
Viruses
β-Interferon
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2204539119