title: RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response.
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.
authors: Ken
authors: K
authors: Takashima
authors: Hiroyuki
authors: H
authors: Oshiumi
authors: Hiromi
authors: H
authors: Takaki
authors: Misako
authors: M
authors: Matsumoto
authors: Tsukasa
authors: T
authors: Seya
mesh_terms: D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D008457:Measles / Q000235:genetics* / Q000821:virology; D008459:Measles virus / Q000235:genetics / Q000472:pathogenicity; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D012330:RNA, Double-Stranded / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics
chemical_list: D007370:Interferon Type I; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D017346:Protein Serine-Threonine Kinases; C534426:RIO kinase 3, human; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1