Host mRNA deadenylation machinery selectively targets interferon mRNAs, regulating antiviral immunity

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Abstract Elucidating host-mediated regulation of viral infection is critical in the development of antivirals and in understanding viral pathogenesis. Here, through high-throughput RNA interference screening, we determine that CNOT2 promotes SARS-CoV-2 infection in human respiratory epithelial cells. CNOT2 is a non-enzymatic subunit of the CCR4-NOT complex, which plays conserved roles in the control of gene expression by deadenylating the poly(A) tails of host mRNAs, thus targeting them for decay. CCR4-NOT can selectively degrade cohorts of mRNAs that are delivered by RNA Binding Proteins. Tristetraprolin (TTP) is among the best characterized of such cargo adapters and is known to recruit mRNAs containing AU-rich elements in their 3′ UTR to CCR4-NOT for deadenylation and decay. We found that in addition to CNOT2, another non-catalytic subunit of CCR4-NOT, CNOT1, in addition to the selectivity factor, TTP, also promote SARS-CoV-2 infection. Global transcriptomics revealed that CNOT2, CNOT1, and TTP specifically regulate interferons (IFNs) and interferon stimulated genes (ISGs) and that depletion of these mRNA decay factors leads to increased levels of IFNs and ISGs. Moreover, the pro-viral activity of CCR4-NOT components and TTP is dependent on IFN signaling: the CCR4-NOT complex has no effect on SARS-CoV-2 infection when IFN signaling is blocked. This led us to discover that CNOT2 promotes the selective deadenylation of IFN mRNAs, and that 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. Supported by grants from NIH (T32-AI-007324)

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