内质网
脱氮酶
细胞生物学
泛素
炎症
生物
信号转导
TLR4型
化学
脂多糖
免疫学
生物化学
基因
作者
Yao Lu,Ying Qiu,Peng Chen,Haishuang Chang,Luqiang Guo,Fang Zhang,Li Ma,Chi Zhang,Xin Zheng,Jun Xiao,Ruiyue Zhong,Lei Han,Xiaoyan Xu,Yanbo Zhang,Dangsheng Li,Guisheng Zhong,Rosemary J. Boyton,Ying Huang,Yongning He,Ronggui Hu,Bin Wei,Hongyan Wang
出处
期刊:Nature microbiology
日期:2019-09-02
卷期号:4 (12): 2331-2346
被引量:39
标识
DOI:10.1038/s41564-019-0542-2
摘要
The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-κB 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 IκBα deubiquitination, resulting in excessive NF-κB 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.
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