Takashima Ken, Oshiumi Hiroyuki, Takaki Hiromi, Matsumoto Misako, Seya Tsukasa
Cell Rep. 2015 Apr 14;11(2):192-200. doi: 10.1016/j.celrep.2015.03.027.
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.
黑色素瘤分化相关基因5（MDA5）是一种细胞质病毒双链RNA（dsRNA）传感器，可触发I型干扰素（IFN）的产生。MDA5沿着病毒dsRNA组装，导致形成激活线粒体抗病毒信号蛋白（MAVS）衔接蛋白所需的MDA5细丝。最近的一项研究表明，蛋白磷酸酶1α（PP1α）和蛋白磷酸酶1γ（PP1γ）负责使MDA5去磷酸化，并且对其激活至关重要。在此，我们确定RIO激酶3（RIOK3）是一种使MDA5 C末端区域磷酸化的蛋白激酶。在麻疹病毒感染后，RIOK3基因敲除强烈增强了I型干扰素和干扰素诱导基因的表达。相反，RIOK3的异位表达或模拟磷酸化的MDA5-S828D突变减弱了MDA5介导的信号传导。此外，RIOK3介导的MDA5磷酸化损害了MDA5多聚体的形成，表明MDA5 C末端磷酸化干扰了MDA5细丝的形成并抑制了其信号传导。我们的数据揭示了在未感染和病毒感染的细胞中细胞质病毒RNA传感器MDA5激活的潜在调控机制。
