2. Academic Validation
  3. HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection

HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection

  • J Clin Invest. 2020 Dec 1;130(12):6301-6316. doi: 10.1172/JCI138234.
Yu Guo 1 2,  Longjun Li 1 3,  Tao Xu 1,  Xiaomin Guo 4,  Chaoming Wang 1 3,  Yihui Li 1 3,  Yanan Yang 4,  Dong Yang 5,  Bin Sun 5,  Xudong Zhao 5,  Genze Shao 6,  Xiaopeng Qi 1 4
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • 2 School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • 3 Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, China.
  • 4 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5 Laboratory of Animal Tumor Models and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 6 Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
PMID: 33104527 DOI: 10.1172/JCI138234
Abstract

The mechanism by which inflammasome activation is modulated remains unclear. In this study, we identified an AIM2-interacting protein, the E3 ubiquitin Ligase HUWE1, which was also found to interact with NLRP3 and NLRC4 through the HIN domain of AIM2 and the NACHT domains of NLRP3 and NLRC4. The BH3 domain of HUWE1 was important for its interaction with NLRP3, AIM2, and NLRC4. Caspase-1 maturation, IL-1β release, and Pyroptosis were reduced in Huwe1-deficient bone marrow-derived macrophages (BMDMs) compared with WT BMDMs in response to stimuli to induce NLRP3, NLRC4, and AIM2 inflammasome activation. Furthermore, the activation of NLRP3, NLRC4, and AIM2 inflammasomes in both mouse and human cells was remarkably reduced by treatment with the HUWE1 inhibitor BI8622. HUWE1 mediated the K27-linked polyubiquitination of AIM2, NLRP3, and NLRC4, which led to inflammasome assembly, ASC speck formation, and sustained Caspase-1 activation. Huwe1-deficient mice had an increased Bacterial burden and decreased Caspase-1 activation and IL-1β production upon Salmonella, Francisella, or Acinetobacter baumannii Infection. Our study provides insights into the mechanisms of inflammasome activation as well as a potential therapeutic target against Bacterial infection.

Keywords

Immunology; Inflammation; Innate immunity; Macrophages; Ubiquitin-proteosome system.

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