The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3.
The Yersinia Type III secretion effector YopM Is an E3 ubiquitin ligase that induced necrotic cell death by targeting NLRP3.
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Yersinia III 型分泌效应子 YopM 是一种 E3 泛素连接酶，通过靶向 NLRP3 诱导坏死细胞死亡
DOI：
10.1038/cddis.2016.413
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发表时间：
2016-12-08
影响因子：
9
通讯作者：
He X
中科院分区：
文献类型：
--
作者：
Wei C;Wang Y;Du Z;Guan K;Cao Y;Yang H;Zhou P;Wu F;Chen J;Wang P;Zheng Z;Zhang P;Zhang Y;Ma S;Yang R;Zhong H;He X
鼠疫耶尔森氏菌使用III型效应蛋白靶向真核生物信号系统。耶尔森氏菌外蛋白（Yop）M效应子来自Y。鼠疫菌是一种重要的毒力决定因子，但它在鼠疫菌中的作用尚不清楚。鼠疫的发病机理才刚刚开始显现。在这里，我们首先确定YopM作为体外细菌IpaH E3连接酶家族的结构模拟物，并确定其N-末端的保守CLD基序负责E3连接酶功能。此外，我们表明NLRP 3是YopM蛋白的新靶点。特别地，YopM与NLRP 3相关联，并且其CLD连接酶基序介导NLRP 3的活化K63连接的泛素化;因此，YopM调节NLRP 3介导的细胞坏死。YopM E3连接酶基序的突变显著降低了Y.鼠疫杆菌诱导HMGB 1释放和细胞坏死，这最终有助于细菌毒力。总之，这项研究已经确定了一个以前未认识到的作用YopM E3连接酶活性的调节宿主细胞坏死和鼠疫发病机制。
Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein. Specially, YopM associates with NLRP3, and its CLD ligase motif mediates the activating K63-linked ubiquitylation of NLRP3; as a result, YopM modulates NLRP3-mediated cell necrosis. Mutation of YopM E3 ligase motif dramatically reduces the ability of Y. pestis to induce HMGB1 release and cell necrosis, which ultimately contributes to bacterial virulence. In conclusion, this study has identified a previously unrecognized role for YopM E3 ligase activity in the regulation of host cell necrosis and plague pathogenesis.