Lu Y, Qiu Y, Chen P, Chang H, Guo L, Zhang F, Ma L, Zhang C, Zheng X, Xiao J, Zhong R, Han L, Xu X, Zhang Y, Li D, Zhong G, Boyton R, Huang Y, He Y, Hu R, Wei B, Wang H

The special organelle-located MAVS, STING and TLR3 are important for clearing viral infections. Although TLR4 triggers NF-?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 ...

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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?B? deubiquitination, resulting in excessive NF-?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.

Date: Dec. 01, 2018

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