ArticleNature microbiology2019
ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection.
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Article in Nature microbiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36citing papers in PubMed
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Who cites it
36 citing papers in PubMed, 57 citations in OpenAlex.
- E3 ubiquitin ligase SYVN1 mediates K63-linked ubiquitination of DDX3X to activate Macrophage NLRP3 Inflammasome.bioRxiv : the preprint server for biology · 2026Article
- Oleic acid alleviates the pathogenesis of lupus by suppressing the activation of TLR signaling pathways through the STAT3/IL-10 axis.Scientific reports · 2026Article
- The host ubiquitination system dynamically regulates the inflammatory response of macrophages to bacteria.Frontiers in immunology · 2026Review
- Endoplasmic reticulum autophagy in inflammatory diseases.Frontiers in immunology · 2026Review
- Ubiquitination by HRD1 is essential for TLR3 trafficking and its innate immune signaling.Nature communications · 2025Article
- USP39 promote post-translational modifiers to stimulate the progress of cancer.Discover oncology · 2025Review
- The Molecular Mechanism by Which miR-129a-3p Targets the TLR4/NF-κB Signaling Pathway to Regulate Inflammatory Damage in 3D4/21 Cells Infected withAnimals : an open access journal from MDPI · 2025Article
- HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress.Molecular and cellular biochemistry · 2024Article
- Casting Light on the Janus-Faced HMG-CoA Reductase Degradation Protein 1: A Comprehensive Review of Its Dualistic Impact on Apoptosis in Various Diseases.Molecular neurobiology · 2024Review
- The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress.iScience · 2024Article
- An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors.British journal of cancer · 2024Article
- Friend or foe? Reciprocal regulation between E3 ubiquitin ligases and deubiquitinases.Biochemical Society transactions · 2024Review
- HRD1-induced TMEM2 ubiquitination promotes ER stress-mediated apoptosis through a non-canonical pathway in intestinal ischemia/reperfusion.Cell death & disease · 2024Article
- DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection.EMBO reports · 2024Article
- Mechanisms of substrate processing during ER-associated protein degradation.Nature reviews. Molecular cell biology · 2023Review
- SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development.Investigative ophthalmology & visual science · 2023Article
- Synoviolin alleviates GSDMD-mediated periodontitis by suppressing its stability.Immunity, inflammation and disease · 2023Article
- SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.Nature cell biology · 2023Article
- Systematic analysis of lysine crotonylation in human macrophages responding to MRSA infection.Frontiers in cellular and infection microbiology · 2023Article
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Authors and funding
22 authors at 8 institutions in 3 countries.
Yao Lu *State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Ying Qiu *State Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Peng ChenState Key Laboratory of Molecule Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Haishuang ChangState Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Luqiang GuoState Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Fang ZhangWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Li MaState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Chi ZhangState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Xin ZhengState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Jun XiaoState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Ruiyue ZhongState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Lei HanState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Xiaoyan XuState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Yanbo ZhangState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Dangsheng LiState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China.
Guisheng ZhongiHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Rosemary BoytonLung Immunology Group, Adult Infectious Disease, Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, UK.
Ying HuangState Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.ORCID http://orcid.org/0000-0002-2806-2874
Yongning HeState Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Ronggui HuState Key Laboratory of Molecule Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. coryhu@sibcb.ac.cn.ORCID http://orcid.org/0000-0001-8323-239X
Bin WeiWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. weibinwhy@shu.edu.cn.ORCID http://orcid.org/0000-0001-8970-3615
Hongyan WangState Key Laboratory of Cell Biology, Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Innovation Center for Cell Signaling Network, Shanghai, China. hongyanwang@sibcb.ac.cn.ORCID http://orcid.org/0000-0002-5781-3745
Center for Excellence in Molecular Cell Science · CNChinese Academy of Sciences · CNShanghai University · CNHarvard University · USNational Institutes of Health · USRoyal Brompton & Harefield NHS Foundation Trust · GBShanghaiTech University · CNTongji University · CN
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
Indexed as
UbiquitinationAnimalsBacterial InfectionsEndoplasmic ReticulumEndoplasmic Reticulum-Associated DegradationGene Knockdown TechniquesHEK293 CellsHumansInflammationLipopolysaccharidesMacrophagesMiceMice, KnockoutProteolysisSalmonella typhimuriumShock, SepticLipopolysaccharidesSyvn1 protein, mouseTlr4 protein, mouseToll-Like Receptor 4Ubiquitin-Protein LigasesUbiquitin-Specific ProteasesUsp15 protein, mouse
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