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

Choi, J.-H.; Zhang, X.; Zhang, C.; Dai, D. L.; Luo, J.; Ladak, R.; Li, Q.; Wiebe, S.; Liu, A. C. H.; Ran, X.; Yang, J.; Naeli, P.; Garzia, A.; Zhou, L.; Mahmood, N.; Deng, Q.; Elaish, M.; Lin, R.; Hobman, T.; Pelletier, J.; Alain, T.; Vidal, S.; Duchaine, T.; Mazhab-Jafari, M.; Mao, X.; Jafarnejad, S. M.; Sonenberg, N.

doi:10.1101/2022.01.19.476693

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bioRxiv · 10.1101/2022.01.19.476693

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

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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-{beta}. 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-{beta} 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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Choi, J.-H., Zhang, X., Zhang, C., Dai, D. L., Luo, J., Ladak, R., Li, Q., Wiebe, S., Liu, A. C. H., Ran, X., Yang, J., Naeli, P., Garzia, A., Zhou, L., Mahmood, N., Deng, Q., Elaish, M., Lin, R., Hobman, T., Pelletier, J., Alain, T., Vidal, S., Duchaine, T., Mazhab-Jafari, M., Mao, X., Jafarnejad, S. M., Sonenberg, N.. 2022-01-20. SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. https://doi.org/10.1101/2022.01.19.476693

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