Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication

Jack Chun Chieh Hsu, Maudry Laurent-Rolle, Joanna B. Pawlak, Hongjie Xia, Amit Kunte, Jia Shee Hee, Jaechul Lim, Lawrence D. Harris, James M. Wood, Gary B. Evans, Pei Yong Shi, Tyler L. Grove, Steven C. Almo, Peter Cresswell

Research output: Contribution to journalArticlepeer-review

Abstract

Innate immune responses induce hundreds of interferon-stimulated genes (ISGs). Viperin, a member of the radical S-adenosyl methionine (SAM) superfamily of enzymes, is the product of one such ISG that restricts the replication of a broad spectrum of viruses. Here, we report a previously unknown antiviral mechanism in which viperin activates a ribosome collision-dependent pathway that inhibits both cellular and viral RNA translation. We found that the radical SAM activity of viperin is required for translation inhibition and that this is mediated by viperin's enzymatic product, 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP). Viperin triggers ribosome collisions and activates the MAPKKK ZAK pathway that in turn activates the GCN2 arm of the integrated stress response pathway to inhibit translation. The study illustrates the importance of translational repression in the antiviral response and identifies viperin as a translation regulator in innate immunity.

Original languageEnglish (US)
Pages (from-to)1631-1642.e6
JournalMolecular Cell
Volume82
Issue number9
DOIs
StatePublished - May 5 2022

Keywords

  • Kunjin virus
  • Zika virus
  • antiviral response
  • innate immunity
  • integrated stress response pathway
  • interferon-stimulated gene
  • ribosome collision
  • translational regulation
  • viperin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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