NUDT2 initiates viral RNA degradation by removal of 5'-phosphates

Nat Commun. 2021 Nov 25;12(1):6918. doi: 10.1038/s41467-021-27239-y.

Abstract

While viral replication processes are largely understood, comparably little is known on cellular mechanisms degrading viral RNA. Some viral RNAs bear a 5'-triphosphate (PPP-) group that impairs degradation by the canonical 5'-3' degradation pathway. Here we show that the Nudix hydrolase 2 (NUDT2) trims viral PPP-RNA into monophosphorylated (P)-RNA, which serves as a substrate for the 5'-3' exonuclease XRN1. NUDT2 removes 5'-phosphates from PPP-RNA in an RNA sequence- and overhang-independent manner and its ablation in cells increases growth of PPP-RNA viruses, suggesting an involvement in antiviral immunity. NUDT2 is highly homologous to bacterial RNA pyrophosphatase H (RppH), a protein involved in the metabolism of bacterial mRNA, which is 5'-tri- or diphosphorylated. Our results show a conserved function between bacterial RppH and mammalian NUDT2, indicating that the function may have adapted from a protein responsible for RNA turnover in bacteria into a protein involved in the immune defense in mammals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Antiviral Agents
  • Bone Marrow Cells
  • CRISPR-Cas Systems
  • Exonucleases
  • Exoribonucleases
  • Female
  • Gene Knockout Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity, Innate
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Polyphosphates
  • RNA Stability*
  • RNA, Bacterial
  • RNA, Messenger
  • RNA, Viral / metabolism*
  • Virus Replication

Substances

  • Antiviral Agents
  • Microtubule-Associated Proteins
  • Polyphosphates
  • RNA, Bacterial
  • RNA, Messenger
  • RNA, Viral
  • Exonucleases
  • Exoribonucleases
  • XRN1 protein, human
  • Phosphoric Monoester Hydrolases
  • NUDT2 protein, human
  • triphosphoric acid