PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome
PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome
复制标题
Spata2-CYLD 的 PLK4 去泛素化抑制中心体处 NEK7 介导的 NLRP3 炎性体激活
DOI：
10.15252/embj.2019102201
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发表时间：
2019-11-25
期刊：
影响因子：
11.4
通讯作者：
Su, Bing
中科院分区：
文献类型：
--
作者：
Yang, Xiao-Dong;Li, Wenguo;Su, Bing
先天免疫传感器NLRP 3与NEK 7和ASC组装炎性体复合物以激活半胱天冬酶-1并驱动促炎细胞因子IL-1 β和IL-18的成熟。必须严格控制NLRP 3炎性体活性，因为其过度活化涉及炎性疾病的发病机制。在这里，我们表明，NLRP 3炎性小体激活被中心体蛋白Spata 2抑制。Spata 2缺陷增强巨噬细胞和腹膜炎动物模型中的NLRP 3炎性体活性。Spata 2在机制上将去泛素化酶CYLD募集到中心体，用于polo样激酶4（PLK 4）的去泛素化，PLK 4是中心体复制的主要调节因子。PLK 4的去泛素化促进其在Ser 204处与NEK 7的结合和磷酸化。NEK 7磷酸化反过来减弱NEK 7和NLRP 3相互作用，这是NLRP 3炎性小体激活所必需的。药理学或shRNA介导的PLK 4抑制，或NEK 7 Ser 204磷酸化位点的突变，增强了NEK 7与NLRP 3的相互作用，并导致NLRP 3炎性体活化增加。我们的研究揭示了一种新的中心体调节炎症体激活的途径，并可能为治疗NLRP 3相关的炎症性疾病提供新的治疗靶点。
The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1 beta and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its over-activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo-like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.