Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases
Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases
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DOI：
10.1126/sciimmunol.abe2933
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发表时间：
2021-04-01
影响因子：
24.8
通讯作者：
Yin, Rong-Hua
中科院分区：
文献类型：
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作者：
Ren, Guang-Ming;Li, Jian;Yin, Rong-Hua
通过抑制核苷酸结合域和富含亮氨酸重复序列(NLR)家族，吡咯结构域包含蛋白3(NLRP3)的炎症体激活在多种临床前炎症性疾病模型中显示出强大的治疗效果。NLRP3去泛素化对于有效的NLRP3炎性小体活动是必不可少的，但目前还不清楚这一过程是否可以用于治疗。在这里，我们证明了硫蛋白(THL)，JAB1/MPN/Mov34(JAMM)结构域的抑制剂，在纳摩尔浓度下通过规范、非规范、替代和转录无关的途径阻止NLRP3炎症体激活。此外，Thl有效地抑制了与低温比林相关的周期性综合征(CAPS)相关的多个NLRP3突变体的激活。在脂多糖诱导的脓毒症、尿酸单钠诱导的腹膜炎、实验性自身免疫性脑脊髓炎、CAPS和蛋氨酸胆碱缺乏饮食诱导的非酒精性脂肪性肝病的小鼠模型中，THL的治疗可以减轻NLRP3相关疾病。机制研究表明，Thl抑制BRCC3异肽复合体(BRISC)介导的NLRP3去泛素化和激活。此外，我们还发现，作为Thl的天然甲基衍生物，Holmycin对NLRP3炎症体的抑制活性甚至比Thl更高。我们的研究证实，NLRP3的翻译后修饰可以在药理学上靶向预防或治疗NLRP3相关的炎症性疾病。未来Thl衍生物的临床开发可能为NLRP3相关疾病提供新的治疗方法。
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.