吡喃结构域
炎症体
NALP3
炎症
医学
免疫学
癌症研究
药理学
化学
作者
Guangming Ren,Jian Li,Xiaochun Zhang,Yu Wang,Xiao Yang,Xuanyi Zhang,Xian Liu,Wen Zhang,Wenbing Ma,Jie Zhang,Yating Li,Shou-Song Tao,Ting Wang,Kai Li,Hui Chen,Zhan Yao,Miao Yu,Chang‐Yan Li,Chang‐Hui Ge,Bo Tian,Guifang Dou,Xiaoming Yang,Rong‐Hua Yin
出处
期刊:Science immunology
[American Association for the Advancement of Science (AAAS)]
日期:2021-04-02
卷期号:6 (58)
被引量:37
标识
DOI:10.1126/sciimmunol.abe2933
摘要
Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate-induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)-mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to prevent or treat NLRP3-associated inflammatory diseases. Future clinical development of derivatives of THL may provide new therapies for NLRP3-related diseases.
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