ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection
ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection
复制标题
内质网定位的 Hrd1 泛素化并灭活 Usp15，促进细菌感染期间 TLR4 诱导的炎症
DOI：
10.1038/s41564-019-0542-2
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发表时间：
2019-12-01
影响因子：
28.3
通讯作者：
Wang, Hongyan
中科院分区：
文献类型：
--
作者：
Lu, Yao;Qiu, Ying;Wang, Hongyan
位于细胞器中的MAVS、STING和TLR 3对清除病毒感染具有重要作用。尽管TLR 4触发NF-κ B活化以产生用于细菌清除的促炎细胞因子，但尚未鉴定具有特殊细胞器定位的效应物。在这里，我们筛选了超过280种E3泛素连接酶，发现位于内质网的Hrd 1在细菌感染期间调节TLR 4诱导的炎症。Hrd 1直接与去泛素化酶Usp 15相互作用。与Hrd 1在内质网相关降解中的经典功能不同，Usp 15不被降解，但失去了I κ B α去泛素化的去泛素化活性，导致过度的NF-κ B活化。重要的是，巨噬细胞中的Hrd 1缺陷保护小鼠免受脂多糖诱导的脓毒性休克，并且在Hrd 1敲除的巨噬细胞中敲低Usp 15恢复减少的IL-6产生。这项研究提出，Hrd 1和TLR 4之间存在串扰，从而在细菌感染期间连接内质网-质膜功能。
The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-kappa B activation to produce pro-inflammatory cytokines for bacterial clearance, effectors with special organelle localization have not been identified. Here, we screened more than 280 E3 ubiquitin ligases and discovered that the endoplasmic reticulum-located Hrd1 regulates TLR4-induced inflammation during bacterial infection. Hrd1 interacts directly with the deubiquitinating enzyme Usp15. Unlike the classical function of Hrd1 in endoplasmic reticulum-associated degradation, Usp15 is not degraded but loses its deubiquitinating activity for I kappa B alpha deubiquitination, resulting in excessive NF-kappa B activation. Importantly, Hrd1 deficiency in macrophages protects mice against lipopolysaccharide-induced septic shock, and knockdown of Usp15 in Hrd1-knockout macrophages restores the reduced IL-6 production. This study proposes that there is crosstalk between Hrd1 and TLR4, thereby linking the endoplasmic reticulum-plasma membrane function during bacterial infection.