Structural insight into the recognition of the linear ubiquitin assembly complex by <i>Shigella</i> E3 ligase IpaH1.4/2.5
Structural insight into the recognition of the linear ubiquitin assembly complex by <i>Shigella</i> E3 ligase IpaH1.4/2.5
复制标题
志贺氏菌 E3 连接酶 IpaH1.4/2.5 识别线性泛素组装复合物的结构洞察
DOI：
10.1093/jb/mvac109
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mizushima Tsunehiro
中科院分区：
文献类型：
--
作者：
Hiragi Keito;Nishide Akira;Takagi Kenji;Iwai Kazuhiro;Kim Minsoo;Mizushima Tsunehiro
病原菌将称为效应子的毒力因子递送到宿主细胞中以促进感染。志贺氏菌效应蛋白IpaH 1.4和IpaH 2.5是“新型E3连接酶”（NEL）型细菌E3连接酶家族的成员。这些蛋白质泛素化线性泛素组装复合物（LUBAC）以抑制核因子（NF）-κB活化，并伴随炎症反应。然而，IpaH1.4和IpaH2.5与LUBAC之间相互作用和识别的分子机制尚不清楚。在这里，我们提出了IpaH1.4和IpaH2.5的基板识别域的晶体结构，分辨率分别为1.4和3.4 μ m。IpaH1.4上的LUBAC结合位点是基于与其他NEL型E3结构的结构比较而预测的。收集并分析结构和生化数据，以确定参与与LUBAC相互作用并影响NF-κB信号传导的IpaH 1.4的特定残基。这里提出的新结构见解表明了细菌病原体如何靶向先天免疫信号通路。
Pathogenic bacteria deliver virulence factors called effectors into host cells in order to facilitate infection. TheShigellaeffector proteins IpaH1.4 and IpaH2.5 are members of the ‘novel E3 ligase’ (NEL)-type bacterial E3 ligase family. These proteins ubiquitinate the linear ubiquitin assembly complex (LUBAC) to inhibit nuclear factor (NF)-κB activation and, concomitantly, the inflammatory response. However, the molecular mechanisms underlying the interaction and recognition between IpaH1.4 and IpaH2.5 and LUBAC are unclear. Here we present the crystal structures of the substrate-recognition domains of IpaH1.4 and IpaH2.5 at resolutions of 1.4 and 3.4 Å, respectively. The LUBAC-binding site on IpaH1.4 was predicted based on structural comparisons with the structures of other NEL-type E3s. Structural and biochemical data were collected and analysed to determine the specific residues of IpaH1.4 that are involved in interactions with LUBAC and influence NF-κB signaling. The new structural insight presented here demonstrates how bacterial pathogens target innate immune signaling pathways.