MRNA 3’UTR lengthening by alternative polyadenylation attenuates inflammatory responses and correlates with virulence of Influenza A virus

ABSTRACT: Alternative polyadenylation (APA) leading to changes of mRNA 3’UTRs has been associated to numerous pathologies but its molecular origin and functional consequences often remain enigmatic. We show that all Influenza A virus (IAV) strains cause APA of host transcripts and mapped the effect to a drug-targetable glycine residue (G184) in the viral non-structural protein 1 (NS1) that is required for its interaction with CPSF4. Unexpectedly, this interaction is also conserved in IAVs not causing virus-induced transcriptional shutoff and introduction of G184R in NS1 alleviates APA. Functionally, a recombinant PR8 (NS1-G184R) virus elicited increased secretion of inflammatory cytokines as compared to the parental wild-type in vitro and in vivo, and had a strongly attenuated phenotype in vivo. Finally, we show that many pathogens induce APA, which is potentially used towards similar immunomodulatory effects.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Valter Bergant  

LAB HEAD: Andreas Pichlmair

PROVIDER: PXD040456 | Pride | 2023-07-12

REPOSITORIES: Pride