HUWE1 mediates inflammasome activation and promotes host defense against bacterial infection.

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.

• Authors: Yu Guo, Longjun Li, Tao Xu, Xiaomin Guo, Chaoming Wang, Yihui Li, Yanan Yang, Dong Yang, Bin Sun, Xudong Zhao, Genze Shao, Xiaopeng Qi
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 12 Pg. 6301-6316 (12 01 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 33104527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AIM2 protein, human
• Aim2 protein, mouse
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Calcium-Binding Proteins
• DNA-Binding Proteins
• IL1B protein, human
• IL1B protein, mouse
• Inflammasomes
• Interleukin-1beta
• Ipaf protein, mouse
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRC4 protein, human
• NLRP3 protein, human
• Nlrp3 protein, mouse
• Tumor Suppressor Proteins
• HUWE1 protein, human
• Huwe1 protein, mouse
• Ubiquitin-Protein Ligases
• Casp1 protein, mouse
• Caspase 1

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, immunology)
• Bacteria (immunology)
• Bacterial Infections (genetics, immunology)
• CARD Signaling Adaptor Proteins (genetics, immunology)
• Calcium-Binding Proteins (genetics, immunology)
• Caspase 1 (genetics, immunology)
• DNA-Binding Proteins (genetics, immunology)
• HEK293 Cells
• Humans
• Inflammasomes (genetics, immunology)
• Interleukin-1beta (genetics, immunology)
• Macrophages (immunology, microbiology)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, immunology)
• Tumor Suppressor Proteins (genetics, immunology)
• Ubiquitin-Protein Ligases (genetics, immunology)