Components of host mRNA decay can promote deadenylation of interferon mRNAs, facilitating viral infection.

Elucidating host-mediated regulation of viral infection is critical in the development of antivirals and in understanding viral pathogenesis. Here, through high-throughput genetic screening, we determine that three components of host mRNA deadenylation, CNOT2, CNOT1, and TTP, promote SARS-CoV-2 infection in human respiratory epithelial cells. Global transcriptomics revealed that CNOT2, CNOT1, and TTP specifically regulate mRNAs in the interferon (IFN) signaling pathway. Moreover, the CCR4-NOT complex has no effect on SARS-CoV-2 infection when IFN signaling is blocked, and depletion of CNOT2 leads to increased poly(A) tail lengths of IFN mRNAs. Therefore, we found that the basal levels of IFNs, and thus IFN signaling, are post-transcriptionally regulated by deadenylation machinery, which in turn impacts susceptibility to viral infections including SARS-CoV-2.