Cell Report：日本科学家发现抗病毒免疫新机制（附原文）

hsu86

4 o9 l# w" p$ V8 n" P& Q
' l4 d. n6 A+ h, [; P% b3 x    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。 ' {4 p! q/ O1 `: z
    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。$ E! o* ~4 K) \0 Z" E" l% W

. |* t, [4 ?- b) h0 Y+ u1 cRIOK3-Mediated Phosphorylation of MDA5 Interferes with Its Assembly and Attenuates the Innate Immune Response
0 [5 W  I, S: d* K* ]0 ] 2 a" a3 w5 j* i2 U# H) j: Y
Ken Takashima, Hiroyuki Oshiumi, Hiromi Takaki, Misako Matsumoto, and Tsukasa Seya5 q8 P+ L" o# z4 O: ^- x. a; v
+ Z. `( \2 p1 `! [8 f
Summary
- e# C0 }$ Z1 O1 I# d+ VMDA5 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.
5 k' k8 z9 r6 M% `5 h4 c5 G& L8 D( N( L0 ~! j1 U( H$ ~( Y

5 h) Z& z4 @) ?! N# E) Z4 n全文下载：
+ S. K; J! n: t0 k/ D7 Q& i4 Y% @, P1 g, }; R% I/ Z  D; T+ O, V

# m, G# I/ t8 m0 Z7 B, n) Y% B3 u% p8 e" g/ [' E8 g3 A8 a1 T
1 F! H5 k4 L- K