XRN1 supplies free nucleotides to feed alphavirus replication

Several RNA viruses induce widespread degradation of cellular mRNAs upon infection; however, the biological significance and mechanistic details of this phenomenon remain unknown. Here, we make use of a model alphavirus, Sindbis virus (SINV), to fill this knowledge gap. We found that SINV triggers cellular RNA decay through the exonuclease XRN1 and the 5’-to-3’ degradation machinery (5-3DM). These proteins accumulate at viral replication organelles (VROs) and interact with the non-structural protein 1 (nsP1), bringing mRNA degradation into proximity with vRNA synthesis. Our data suggest that monophosphate nucleotides released by cellular RNA decay are recycled through the salvage pathway to feed viral replications. Our work thus reveals a fundamental connection between cellular mRNA degradation and viral replication via nucleotides repurposing. Research highlights 5’-3’ RNA decay is essential for the replication of a wide range of viruses. XRN1 directly interacts with transcripts which are degraded during infection. RNA decay factors and salvage pathway members localise to viral factories. Supplying nucleosides to several 5-3DM deficient cells facilitates SINV infection.