Cell Report：日本科学家发现抗病毒免疫新机制（附原文）

hsu86

* ^3 @* q% ^2 L0 z6 S2 f1 O

9 S% X) \: I: F6 U" k    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。
: m/ U5 w; y0 f. T. G    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。+ m; G$ f& G( E/ G

8 t7 R9 Z8 }# RRIOK3-Mediated Phosphorylation of MDA5 Interferes with Its Assembly and Attenuates the Innate Immune Response3 ]: J2 f+ @/ [, x8 o+ B

( E: ]) m3 K1 M: {6 V) MKen Takashima, Hiroyuki Oshiumi, Hiromi Takaki, Misako Matsumoto, and Tsukasa Seya. X% @; b8 r  A) i$ Y. ~

* X2 h2 t4 e5 F# i: t, a5 _Summary! S$ P8 e  q: o. m; L: h6 s) v; b9 {# I
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.% g" g9 }; E9 h

( t/ Z' ]$ h3 O0 M- t6 A- f! F7 s- O- ]2 n! u& }# a( L6 t$ R7 K( L5 c
全文下载：7 P$ _, J/ L) [2 j, p0 G
- {8 Q/ W# v8 E7 z- V

7 ^) C! s; T3 y* J
1 {* Y" O  E& n# A
: f5 m) w# _4 \% s5 F7 S" h- o; @