RIOK3-Mediated Phosphorylation of MDA5 Interferes with Its Assembly and Attenuates the Innate Immune Response

Ken Takashima, Hiroyuki Oshiumi, Hiromi Takaki, Misako Matsumoto, and Tsukasa Seya


Highlights
•RIOK3 attenuates MDA5-mediated innate immune response
•RIOK3 mediates phosphorylation of MDA5 Ser-828
•Phosphorylation of MDA5 Ser-828 disrupts its assembly and signaling
Summary
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.

http://www.cell.com/cell-reports/abstract/S2211-1247(15)00296-X