SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

Viral infection involves complex set of events orchestrated by multiple viral proteins. To identify functions of SARS-CoV-2 proteins, we performed transcriptomic analyses of cells expressing individual viral proteins. Expression of Nsp14, a protein involved in viral RNA replication, provoked a dramatic remodeling of the transcriptome that strongly resembled that observed following SARS-CoV-2 infection. Moreover, Nsp14 expression altered the splicing of more than 1000 genes and resulted in a dramatic increase in the number of circRNAs, which are linked to innate immunity. These effects were independent of the Nsp14 exonuclease activity and required the N7-guanine-methyltransferase domain of the protein. Activation of the NFkB pathway and increased expression of CXCL8 occurred early upon Nsp14 expression. We identified IMPDH2, which catalyzes the rate-limiting step of guanine nucleotides biosynthesis, as a key mediator of these effects. Nsp14 expression caused an increase in GTP cellular levels, and the effect of Nsp14 was strongly decreased in the presence of IMPDH2 inhibitors. Together, our data demonstrate an unknown role for Nsp14 with implications for therapy.

Automated summary

Viral infection involves a complex set of events orchestrated by multiple viral proteins. In this study, the researchers focused on the functions of Nsp14, a protein involved in viral RNA replication. They found that the expression of Nsp14 caused significant changes in the transcriptome and splicing of genes, as well as an increase in circRNAs. These effects were independent of Nsp14's exonuclease activity and required the N7-guanine-methyltransferase domain of the protein. Activation of the NFkB pathway and increased expression of CXCL8 were observed early upon Nsp14 expression. The researchers identified IMPDH2 as a key mediator of these effects, suggesting its involvement in guanine nucleotides biosynthesis. Overall, this study reveals a previously unknown role for Nsp14 with implications for therapy.