Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production

Mol Cell. 2015 Apr 2;58(1):134-46. doi: 10.1016/j.molcel.2015.01.036. Epub 2015 Mar 5.

Abstract

RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.

Publication types

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

MeSH terms

  • Amides / metabolism
  • Animals
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / genetics
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / immunology*
  • Cell Line
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / antagonists & inhibitors
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology*
  • DEAD-box RNA Helicases / metabolism
  • Enzyme Activation
  • Fibroblasts / enzymology
  • Fibroblasts / immunology
  • Fibroblasts / virology
  • Gammaherpesvirinae / genetics
  • Gammaherpesvirinae / immunology*
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Immune Evasion / genetics*
  • Immunity, Innate
  • Mice
  • Molecular Mimicry
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Viral / genetics
  • RNA, Viral / immunology*
  • Signal Transduction
  • Viral Proteins / genetics
  • Viral Proteins / immunology*

Substances

  • Amides
  • Cytokines
  • RNA, Small Interfering
  • RNA, Viral
  • Viral Proteins
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
  • phosphoribosylformylglycinamidine synthetase