期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2204539119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
A robust antiviral innate immune response is indispensable for combating infections. However, an exacerbated response can result in pathological inflammation and tissue damage. mRNA translational control mechanisms play a crucial role in maintaining the appropriate magnitude and duration of the immune response. We show that the GIGYF2/4EHP translational repressor complex represses translation of
Ifnb1 mRNA, which encodes type I interferon β (IFN-β). We also demonstrate that the NSP2 protein encoded by SARS-CoV-2 virus further impedes translation of
Ifnb1 mRNA through coopting the GIGYF2/4EHP complex, leading to evasion of a cellular innate immune response. The knowledge of the mechanism of action of NSP2-mediated IFN-β suppression provides valuable information for development of treatments for infections of SARS-CoV-2 and other coronaviruses.
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.
