Cell Report：日本科学家发现抗病毒免疫新机制（附原文）

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    天然免疫应答对于抵抗病毒的感染十分重要。RIG-I与MDA-5是最常见的细胞内部识别病毒RNA的信号分子，它们的识别与激活能够传递胞内的抗病毒免疫反应。MDA-5能够识别较长的双链RNA分子，而RIG-I识别的序列长度较短。对于MDA-5来讲，它由N端的两个CARD结构域，中部的RNA解旋酶结构域以及C端的一个结构域（CTD）构成，其中CTD负责识别胞内的双链病毒RNA分子。随后，MDA-5围绕RNA分子通过蛋白-蛋白相互作用彼此头尾相连，最终形成纤维状的结构。这一结构能够促进CARD的寡聚化，而寡聚化后的CARD复合体则能够进一步结合位于线粒体上的MAVS蛋白进行信号的传递。以前的研究显示MDA5的活性受到其CARD的磷酸化调控，然而内在的分子机制却仍不清楚，同时C端的功能也同样不清楚。
0 n8 E, s( ]) l/ V    最近，来自北海道大学的Tsukasa Seya课题组在《cell report》杂志上发表了他们对MDA-5 C端磷酸化的分子机制以及其作用的相关研究。
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, G' |8 n* @' p& {* d0 A( ]4 }& t0 eRIOK3-Mediated Phosphorylation of MDA5 Interferes with Its Assembly and Attenuates the Innate Immune Response2 p! z: d  J* l+ }

4 ~) c5 W7 R! K8 F. b6 Q0 rKen Takashima, Hiroyuki Oshiumi, Hiromi Takaki, Misako Matsumoto, and Tsukasa Seya6 `: B$ z4 @, i+ S/ Y- }
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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.
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