ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

Elife. 2015 Nov 26;4:e10859. doi: 10.7554/eLife.10859.

Abstract

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding.

Keywords: ATPase domain; RIG-I; RLR; Singleton-Merten Syndrome; autoimmune response / disease; cell biology; human; immunology; innate immune system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism*
  • Humans
  • Hydrolysis
  • RNA, Viral / metabolism*
  • Substrate Specificity

Substances

  • RNA, Viral
  • Adenosine Triphosphate
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases