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 the K63-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.
基金：
Shanghai Municipal Health Commission (202040119
to J.N.), the National Natural Science Foundation of China (81700672 to J.N.;
31670910 to X.W.; 81871912 and 81970530 to Y.W.), grants from the Recruitment
Program of Global Experts of China (to X.W.), startup grants from Shanghai Jiao Tong
University School of Medicine and Shanghai Institute of Immunology (to X.W.), the
Shanghai Jiao Tong University Program for Young Teachers (KJ3-0214-16-0013 to
X.W.; KJ3-0214-19-0011 to J.N.), and a Shanghai Municipal Health Bureau Key
Disciplines Grant (ZK2019C012 to Y.W.).
第一作者机构：[1]Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Dept Immunol & Microbiol, Sch Med, Room 207,Bldg 7 West Area,280 South Chongqing Rd, Shanghai, Peoples R China
通讯作者：
通讯机构：[1]Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Dept Immunol & Microbiol, Sch Med, Room 207,Bldg 7 West Area,280 South Chongqing Rd, Shanghai, Peoples R China[3]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Sch Med, Dept Gastroenterol, 1111 XianXia Rd, Shanghai 200336, Peoples R China[4]Shanghai Jiao Tong Univ, Shanghai Tongren Hosp, Hongqiao Int Inst Med, Sch Med, Shanghai, Peoples R China[5]Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Sch Med, Shanghai, Peoples R China[*1]Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 XianXia Road, Shanghai 200336, China[*2]Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Room 207, Building No. 7 (West Area), No. 280 South Chongqing Road, Shanghai, China
推荐引用方式(GB/T 7714)：
Ni Jun,Guan Chenyang,Liu Hua,et al.Ubc13 Promotes K63-Linked Polyubiquitination of NLRP3 to Activate Inflammasome[J].JOURNAL OF IMMUNOLOGY.2021,206(10):2376-2385.doi:10.4049/jimmunol.2001178.
APA：
Ni, Jun,Guan, Chenyang,Liu, Hua,Huang, Xian,Yue, Jinnan...&Wu, Xuefeng.(2021).Ubc13 Promotes K63-Linked Polyubiquitination of NLRP3 to Activate Inflammasome.JOURNAL OF IMMUNOLOGY,206,(10)
MLA：
Ni, Jun,et al."Ubc13 Promotes K63-Linked Polyubiquitination of NLRP3 to Activate Inflammasome".JOURNAL OF IMMUNOLOGY 206..10(2021):2376-2385
医学