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

Zaffagni, Michela; Harris, Jenna M; Patop, Ines L; Pamudurti, Nagarjuna Reddy; Nguyen, Sinead; Kadener, Sebastian

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 Nsp14 exonuclease activity and the co-factor Nsp10. Activation of the NFkB pathway and increased expression of CXCL8 occurred early upon Nsp14 expression. IMPDH2, which catalyzes the rate-limiting step of guanine biosynthesis, was identified as a key mediator of the effect. Nsp14 expression caused an increase in GTP cellular levels, and the effect of Nsp14 was strongly decreased in presence of an IMPDH2 inhibitor. Together, our data demonstrate an unknown role for Nsp14 with implications for therapy.