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

Beatrice T. Laudenbach, Karsten Krey, Quirin Emslander, Line Lykke Andersen, Alexander Reim, Pietro Scaturro, Sarah Mundigl, Christopher Dächert, Katrin Manske, Markus Moser, Janos Ludwig, Dirk Wohlleber, Andrea Kröger, Marco Binder and Andreas Pichlmair ()
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Beatrice T. Laudenbach: Technical University of Munich, School of Medicine, Institute of Virology
Karsten Krey: Technical University of Munich, School of Medicine, Institute of Virology
Quirin Emslander: Technical University of Munich, School of Medicine, Institute of Virology
Line Lykke Andersen: Technical University of Munich, School of Medicine, Institute of Virology
Alexander Reim: Max-Planck Institute of Biochemistry
Pietro Scaturro: Technical University of Munich, School of Medicine, Institute of Virology
Sarah Mundigl: Technical University of Munich, School of Medicine, Institute of Virology
Christopher Dächert: Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response” (division F170), German Cancer Research Center, Heidelberg (DKFZ)
Katrin Manske: Technical University of Munich, School of Medicine, Institute of Molecular Immunology
Markus Moser: Max-Planck Institute of Biochemistry
Janos Ludwig: University Hospital Bonn
Dirk Wohlleber: Technical University of Munich, School of Medicine, Institute of Molecular Immunology
Andrea Kröger: Otto von Guericke University Magdeburg, Institute for Medical Microbiology
Marco Binder: Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response” (division F170), German Cancer Research Center, Heidelberg (DKFZ)
Andreas Pichlmair: Technical University of Munich, School of Medicine, Institute of Virology

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27239-y

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