ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection
Lu, Yao1; Qiu, Ying1; Chen, Peng2; Chang, Haishuang3; Guo, Luqiang3; Zhang, Fang4,5; Ma, Li1; Zhang, Chi1; Zheng, Xin1; Xiao, Jun1; Zhong, Ruiyue1; Han, Lei1; Xu, Xiaoyan1,6; Zhang, Yanbo1,7; Li, Dangsheng1; Zhong, Guisheng8; Boyton, Rosemary9,10; Huang, Ying3; He, Yongning3; Hu, Ronggui2; Wei, Bin4,5,11; Wang, Hongyan1,11
AbstractThe 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.
Indexed BySCI
Funding ProjectState Key Laboratory of Cell Biology, SIBCB, CAS[SKL CBKF2013003]
WOS Research AreaMicrobiology
WOS SubjectMicrobiology
WOS IDWOS:000499071100035
Original Document TypeArticle
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Cited Times [WOS]:0   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Corresponding AuthorHu, Ronggui; Wei, Bin; Wang, Hongyan
Affiliation1.Chinese Acad Sci, Univ Chinese Acad Sci, Key Lab Syst Biol,State Key Lab Cell Biol,CAS Ctr, Shanghai Inst Biochem & Cell Biol,Innovat Ctr Cel, Shanghai, Peoples R China
2.Chinese Acad Sci, Univ Chinese Acad Sci, State Key Lab Mol Biol,CAS Ctr Excellence Mol Cel, Key Lab Syst Biol,Shanghai Inst Biochem & Cell Bi, Shanghai, Peoples R China
3.Chinese Acad Sci, Univ Chinese Acad Sci,Shanghai Inst Biochem & Cel, Natl Ctr Prot Sci Shanghai,CAS Ctr Excellence Mol, State Key Lab Mol Biol,Shanghai Sci Res Ctr,Shang, Shanghai, Peoples R China
4.Chinese Acad Sci, Wuhan Inst Virol, Wuhan, Hubei, Peoples R China
5.Shanghai Univ, Sch Life Sci, Shanghai, Peoples R China
6.NCI, Expt Immunol Branch, US Natl Inst Hlth, Bethesda, MA USA
7.Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA
8.ShanghaiTech Univ, Sch Life Sci & Technol, iHuman Inst, Shanghai, Peoples R China
9.Imperial Coll London, Fac Med, Dept Infect Dis, Lung Immunol Grp,Adult Infect Dis, London, England
10.Royal Brompton & Harefield NHS Fdn Trust, Dept Resp Med, London, England
11.Tongji Univ, Shanghai Peoples Hosp 10, Canc Ctr, Sch Med, Shanghai, Peoples R China
Recommended Citation
GB/T 7714
Lu, Yao,Qiu, Ying,Chen, Peng,et al. ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection[J]. NATURE MICROBIOLOGY,2019,4(12):2331-2346.
APA Lu, Yao.,Qiu, Ying.,Chen, Peng.,Chang, Haishuang.,Guo, Luqiang.,...&Wang, Hongyan.(2019).ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection.NATURE MICROBIOLOGY,4(12),2331-2346.
MLA Lu, Yao,et al."ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection".NATURE MICROBIOLOGY 4.12(2019):2331-2346.
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