RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response.
RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response.
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DOI：
10.1016/j.celrep.2015.03.027
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发表时间：
2015-04
期刊：
影响因子：
8.8
通讯作者：
Ken Takashima;H. Oshiumi;Hiromi Takaki;M. Matsumoto;T. Seya
中科院分区：
文献类型：
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作者：
Ken Takashima;H. Oshiumi;Hiromi Takaki;M. Matsumoto;T. Seya
MDA 5是细胞质病毒双链RNA（dsRNA）传感器，并触发I型干扰素（IFN）产生。MDA 5沿着病毒dsRNA组装，导致形成激活MAVS衔接子所需的MDA 5细丝。最近的一项研究表明，PP 1 α和PP 1 γ磷酸酶负责MDA 5的去磷酸化，并对其活化至关重要。在此，我们鉴定了RIO激酶3（RIOK 3）作为一种磷酸化MDA 5 C-末端区域的蛋白激酶，RIOK 3敲除强烈增强了麻疹病毒感染后I型IFN和IFN诱导基因的表达。相反，RIOK 3或磷酸化模拟MDA 5-S828 D突变的异位表达减弱了MDA 5介导的信号传导。此外，RIOK 3介导的MDA 5磷酸化损害了MDA 5多聚体的形成，表明MDA 5 C-末端磷酸化干扰了MDA 5细丝的形成并抑制了其信号传导。我们的数据揭示了未感染和病毒感染细胞中细胞质病毒RNA传感器MDA 5激活的调控机制。
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.RIOK3knockout 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.