RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response.
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Takashima K, Oshiumi H, Takaki H, Matsumoto M, Seya T
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.
- PubMed ID
- 25865883 [ View in PubMed]
- 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 PP1alpha and PP1gamma 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.