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

Zhang XuJung-Hyun ChoiDavid L DaiJun LuoReese Jalal LadakQian LiYimeng WangChristine ZhangShane WiebeAlex C H LiuXiaozhuo RanJiaqi YangParisa NaeliAitor GarziaLele ZhouNiaz MahmoodQiyun DengMohamed ElaishRongtuan LinLara K MahalTom C HobmanJerry PelletierTommy AlainSilvia M VidalThomas DuchaineMohammad T Mazhab-JafariXiaojuan MaoSeyed Mehdi JafarnejadNahum Sonenberg
Published in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
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