Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation
Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation
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DOI：
10.1074/jbc.m112.407130
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发表时间：
2012-10-19
影响因子：
4.8
通讯作者：
Alnemri, Emad S.
中科院分区：
文献类型：
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作者：
Juliana, Christine;Fernandes-Alnemri, Teresa;Alnemri, Emad S.
NLRP3炎性小体是先天免疫应答致病性感染和组织损伤的关键组成部分。它还参与许多人类疾病的发病机制，包括痛风性关节炎、矽肺、动脉粥样硬化和2型糖尿病。NLRP3炎性小体的组装需要来自模式识别或细胞因子受体的启动信号，其次是来自细胞外ATP、成孔毒素或晶体物质的第二信号。这两种信号如何激活NLRP3炎性体尚不清楚。本研究表明，在小鼠巨噬细胞中，模式识别受体TLR4通过MyD88发出的信号可以通过刺激NLRP3的去泛素化而快速非转录启动NLRP3。这一过程依赖于线粒体活性氧的产生，可以被抗氧化剂抑制。我们进一步表明，ATP信号也可以通过一种对抗氧化剂不敏感的机制诱导NLRP3的去泛素化。在小鼠和人细胞中，NLRP3去泛素化的药理抑制完全阻断了NLRP3的激活，这表明NLRP3的激活需要去泛素化。我们的研究结果表明NLRP3是由toll样受体信号和线粒体活性氧启动的两步去泛素化机制激活的，并进一步被ATP增强，这可以解释NLRP3是如何被各种危险信号激活的。
The NLRP3 inflammasome is a key component of the innate immune response to pathogenic infection and tissue damage. It is also involved in the pathogenesis of a number of human diseases, including gouty arthritis, silicosis, atherosclerosis, and type 2 diabetes. The assembly of the NLRP3 inflammasome requires a priming signal derived from pattern recognition or cytokine receptors, followed by a second signal derived from extracellular ATP, pore-forming toxins, or crystalline materials. How these two signals activate the NLRP3 inflammasome is not yet clear. Here, we show that in mouse macrophages, signaling by the pattern recognition receptor TLR4 through MyD88 can rapidly and non-transcriptionally prime NLRP3 by stimulating its deubiquitination. This process is dependent on mitochondrial reactive oxygen species production and can be inhibited by antioxidants. We further show that signaling by ATP can also induce deubiquitination of NLRP3 by a mechanism that is not sensitive to antioxidants. Pharmacological inhibition of NLRP3 deubiquitination completely blocked NLRP3 activation in both mouse and human cells, indicating that deubiquitination of NLRP3 is required for its activation. Our findings suggest that NLRP3 is activated by a two-step deubiquitination mechanism initiated by Toll-like receptor signaling and mitochondrial reactive oxygen species and further potentiated by ATP, which could explain how NLRP3 is activated by diverse danger signals.