Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation.
Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation.
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Shigella Flexneri通过抑制线性泛素链连接来抑制NF-κB激活。
DOI：
10.1038/nmicrobiol.2016.84
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发表时间：
2016-05-27
影响因子：
28.3
通讯作者：
Alto, Neal M.
中科院分区：
文献类型：
--
作者：
de Jong, Maarten F.;Liu, Zixu;Chen, Didi;Alto, Neal M.
线性泛素链组装复合物（LUBAC）是一种多聚体E3连接酶，催化活化的免疫受体信号传导复合物（RSC）的M1或线性泛素化。虽然破坏线性泛素组装的突变导致复杂的疾病病理，包括人类和小鼠的免疫缺陷和自身炎症，但尚未发现靶向LUBAC功能的微生物毒素。在这里，我们报告了两个同源志贺氏菌III型分泌系统（T3 SS）效应E3连接酶IpaH1.4和IpaH2.5的鉴定，它们直接与LUBAC亚基HOIL-1 L（RBCK 1）相互作用，并将K48连接的泛素链与HOIP（RNF 31）的催化环间环结构域结合。HOIP的蛋白酶体降解导致响应TNF、IL-1β和病原体相关分子模式（PAMP）的线性泛素化的不可逆失活和NF-κB核转位的钝化。结合细菌遗传学的哺乳动物细胞功能丧失研究解释了志贺氏菌如何通过协同抑制受体泛素化来逃避广谱免疫监视系统，并揭示了LUBAC在宿主防御病原体中的至关重要性。
The Linear Ubiquitin chain Assembly Complex (LUBAC) is a multimeric E3 ligase that catalyzes M1- or linear ubiquitination of activated immune receptor signaling complexes (RSCs). While mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri Type III Secretion System (T3SS) effector E3 ligases IpaH1.4 and IpaH2.5 that directly interact with LUBAC subunit HOIL-1L (RBCK1) and conjugate K48-linked ubiquitin chains to the catalytic RING-between-RING domain of HOIP (RNF31). Proteasomal degradation of HOIP leads to irreversible inactivation of linear ubiquitination and blunting of NF-κB nuclear translocation in response to TNF, IL-1β, and pathogen associated molecular patterns (PAMPs). Loss of function studies in mammalian cells in combination with bacterial genetics explains how Shigella evades a broad spectrum of immune surveillance systems by cooperative inhibition of receptor ubiquitination, and reveals the critical importance of LUBAC in host defense against pathogens.
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影响因子：
6.7
作者：
Ashida H;Nakano H;Sasakawa C
通讯作者：
Sasakawa C
影响因子：
3.6
作者：
Ashida, Hiroshi;Toyotome, Takahito;Sasakawa, Chihiro
通讯作者：
Sasakawa, Chihiro
影响因子：
6.4
作者：
RAQIB, R;WRETLIND, B;LINDBERG, AA
通讯作者：
LINDBERG, AA
影响因子：
16
作者：
Damgaard, Rune Busk;Nachbur, Ueli;Gyrd-Hansen, Mads
通讯作者：
Gyrd-Hansen, Mads
影响因子：
3.1
作者：
Lan, R;Alles, MC;Reeves, PR
通讯作者：
Reeves, PR