PMID- 33104527 OWN - NLM STAT- MEDLINE DCOM- 20210216 LR - 20210302 IS - 1558-8238 (Electronic) IS - 0021-9738 (Print) IS - 0021-9738 (Linking) VI - 130 IP - 12 DP - 2020 Dec 1 TI - HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection. PG - 6301-6316 LID - 138234 [pii] LID - 10.1172/JCI138234 [doi] AB - 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-1beta 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-1beta 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. FAU - Guo, Yu AU - Guo Y AD - 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. AD - School of Life Sciences, University of Science and Technology of China, Hefei, China. FAU - Li, Longjun AU - Li L AD - 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. AD - Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, China. FAU - Xu, Tao AU - Xu T AD - 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. FAU - Guo, Xiaomin AU - Guo X AD - Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Wang, Chaoming AU - Wang C AD - 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. AD - Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, China. FAU - Li, Yihui AU - Li Y AD - 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. AD - Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, China. FAU - Yang, Yanan AU - Yang Y AD - Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. FAU - Yang, Dong AU - Yang D AD - Laboratory of Animal Tumor Models and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China. FAU - Sun, Bin AU - Sun B AD - Laboratory of Animal Tumor Models and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China. FAU - Zhao, Xudong AU - Zhao X AD - Laboratory of Animal Tumor Models and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China. FAU - Shao, Genze AU - Shao G AD - Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. FAU - Qi, Xiaopeng AU - Qi X AD - 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. AD - Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Clin Invest JT - The Journal of clinical investigation JID - 7802877 RN - 0 (AIM2 protein, human) RN - 0 (Aim2 protein, mouse) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (CARD Signaling Adaptor Proteins) RN - 0 (Calcium-Binding Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (IL1B protein, human) RN - 0 (IL1B protein, mouse) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Ipaf protein, mouse) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRC4 protein, human) RN - 0 (NLRP3 protein, human) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.3.2.26 (HUWE1 protein, human) RN - EC 2.3.2.26 (Huwe1 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 3.4.22.36 (Casp1 protein, mouse) RN - EC 3.4.22.36 (Caspase 1) SB - IM MH - Animals MH - Apoptosis Regulatory Proteins/genetics/immunology MH - Bacteria/*immunology MH - Bacterial Infections/genetics/*immunology MH - CARD Signaling Adaptor Proteins/genetics/immunology MH - Calcium-Binding Proteins/genetics/immunology MH - Caspase 1/genetics/immunology MH - DNA-Binding Proteins/genetics/immunology MH - HEK293 Cells MH - Humans MH - Inflammasomes/genetics/*immunology MH - Interleukin-1beta/genetics/immunology MH - Macrophages/*immunology/microbiology MH - Mice MH - Mice, Knockout MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/immunology MH - Tumor Suppressor Proteins/genetics/*immunology MH - Ubiquitin-Protein Ligases/genetics/*immunology PMC - PMC7685759 OTO - NOTNLM OT - Immunology OT - Inflammation OT - Innate immunity OT - Macrophages OT - Ubiquitin-proteosome system COIS- Conflict of interest: The authors have declared that no conflict of interest exists. EDAT- 2020/10/27 06:00 MHDA- 2021/02/17 06:00 PMCR- 2021/03/01 CRDT- 2020/10/26 17:13 PHST- 2020/03/17 00:00 [received] PHST- 2020/08/11 00:00 [accepted] PHST- 2020/10/27 06:00 [pubmed] PHST- 2021/02/17 06:00 [medline] PHST- 2020/10/26 17:13 [entrez] PHST- 2021/03/01 00:00 [pmc-release] AID - 138234 [pii] AID - 10.1172/JCI138234 [doi] PST - ppublish SO - J Clin Invest. 2020 Dec 1;130(12):6301-6316. doi: 10.1172/JCI138234.