Ubc13 Promotes K63-Linked Polyubiquitination of NLRP3 to Activate Inflammasome
| Autor: | Yugang Wang, Jinnan Yue, Hongrui Xiang, Xian Huang, Jun Ni, Chenyang Guan, Hua Liu, Wenyi Cao, Xuefeng Wu, Jiamin Liu, Zhengting Wang, Yuexiao Tao, Zhenyan Jiang |
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| Rok vydání: | 2021 |
| Předmět: |
Inflammasomes
Immunology Lysine Mice Transgenic Transfection Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Immunology and Allergy Polyubiquitin chemistry.chemical_classification Gene knockdown Innate immune system integumentary system biology Macrophages Ubiquitination Inflammasome Cell biology HEK293 Cells Enzyme chemistry Ubiquitin-Conjugating Enzymes biology.protein Protein Binding 030215 immunology Deubiquitination medicine.drug |
| Zdroj: | The Journal of Immunology. 206:2376-2385 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2001178 |
| Popis: | NLRP3 inflammasome plays an important role in innate immune system through recognizing pathogenic microorganisms and danger-associated molecules. Deubiquitination of NLRP3 has been shown to be essential for its activation, yet the functions of Ubc13, the K63-linked specific ubiquitin-conjugating enzyme E2, in NLRP3 inflammasome activation are not known. In this study, we found that in mouse macrophages, Ubc13 knockdown or knockout dramatically impaired NLRP3 inflammasome activation. Catalytic activity is required for Ubc13 to control NLRP3 activation, and Ubc13 pharmacological inhibitor significantly attenuates NLRP3 inflammasome activation. Mechanistically, Ubc13 associates with NLRP3 and promotes its K63-linked polyubiquitination. Through mass spectrum and biochemical analysis, we identified lysine 565 and lysine 687 as theK63-linked polyubiquitination sites of NLRP3. Collectively, our data suggest that Ubc13 potentiates NLRP3 inflammasome activation via promoting site-specific K63-linked ubiquitination of NLRP3. Our study sheds light on mechanisms of NLRP3 inflammasome activation and identifies that targeting Ubc13 could be an effective therapeutic strategy for treating aberrant NLRP3 inflammasome activation–induced pathogenesis. |
| Databáze: | OpenAIRE |
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