UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression.
UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression.
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UAF1 去泛素酶复合物通过促进 NLRP3 表达来促进 NLRP3 炎性体激活。
DOI：
10.1038/s41467-020-19939-8
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发表时间：
2020-11-27
影响因子：
16.6
通讯作者：
Zhao W
中科院分区：
文献类型：
--
作者：
Song H;Zhao C;Yu Z;Li Q;Yan R;Qin Y;Jia M;Zhao W
NOD样受体蛋白3(NLRP3)检测微生物感染或内源性危险信号，激活NLRP3炎症小体，在宿主防御中具有重要作用，参与炎症性疾病的发病，因此需要严格控制。NLRP3去泛素化被认为是NLRP3炎性小体激活的关键步骤。然而，去泛素化控制NLRP3炎症体激活的机制尚不清楚。在这里，我们证明了UAF1/USP1去泛素酶复合体选择性地移除K48连接的NLRP3的多泛素化并抑制其泛素化介导的降解，提高细胞内NLRP3的水平，这是后续NLRP3炎症体组装和激活所必需的。此外，UAF1/USP12和UAF1/USP46复合体通过抑制泛素化介导的p65降解，促进NF-κB的激活，增强NLRP3和促炎细胞因子(包括前IL-1β、肿瘤坏死因子和IL-6)的转录。因此，在体外和体内，UAF1缺乏均可抑制NLRP3炎症体的激活和IL-1β的分泌。我们的研究表明，UAF1脱泛素酶复合体通过靶向NLRP3和P65并许可NLRP3炎症体激活来增强NLRP3和前IL-1β的表达。NLRP3炎症体的激活受到各种信号通路的调节，以确保炎症不会失控。在这里，作者展示了去泛素化如何通过UAF1/USP去泛素酶复合体的功能来避免这一调节来激活NLRP3炎症体。
NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation. NLRP3 inflammasome activation is regulated by various signaling pathways to ensure inflammation does not go unchecked. Here the authors show how deubiquitination avoids this regulation to activate the NLRP3 inflammasome through the function of UAF1/USP deubiquitinase complexes.
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