RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response

Cell Rep. 2015 Apr 14;11(2):192-200. doi: 10.1016/j.celrep.2015.03.027.

Abstract

MDA5 is a cytoplasmic viral double-stranded RNA (dsRNA) sensor and triggers type I interferon (IFN) production. MDA5 assembles along viral dsRNA, leading to the formation of an MDA5 filament required for activating the MAVS adaptor. A recent study has revealed that PP1α and PP1γ phosphatases are responsible for dephosphorylating MDA5 and are essential for its activation. Here, we identified RIO kinase 3 (RIOK3) as a protein kinase that phosphorylates the MDA5 C-terminal region. RIOK3 knockout strongly enhanced type I IFN and IFN-inducible gene expression following measles virus infection. Conversely, the ectopic expression of RIOK3 or a phosphomimetic MDA5-S828D mutation attenuated MDA5-mediated signaling. Moreover, RIOK3-mediated MDA5 phosphorylation impaired MDA5 multimer formation, indicating that MDA5 C-terminal phosphorylation interferes with MDA5 filament formation and suppresses its signaling. Our data revealed a regulatory mechanism underlying the activation of the cytoplasmic viral RNA sensor MDA5 in both uninfected and virus-infected cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DEAD-box RNA Helicases / biosynthesis
  • DEAD-box RNA Helicases / genetics*
  • HEK293 Cells
  • Humans
  • Immunity, Innate / genetics*
  • Interferon Type I / biosynthesis
  • Interferon Type I / genetics
  • Interferon-Induced Helicase, IFIH1
  • Measles / genetics*
  • Measles / virology
  • Measles virus / genetics
  • Measles virus / pathogenicity
  • Mutation
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / genetics*
  • RNA, Double-Stranded / genetics
  • RNA, Viral / genetics

Substances

  • Interferon Type I
  • RNA, Double-Stranded
  • RNA, Viral
  • Protein Serine-Threonine Kinases
  • RIO kinase 3, human
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1