NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation
NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation
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NLRP3 磷酸化是炎症小体激活的重要启动事件。
DOI：
10.1016/j.molcel.2017.08.017
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发表时间：
2017-10-05
期刊：
影响因子：
16
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Song, Nan;Liu, Zhao-Shan;Li, Tao
许多感染和应激信号可以快速激活NLRP 3炎性体，引发强烈的炎症反应。这种激活需要引发步骤，其被认为主要用于上调NLRP 3转录。然而，最近的研究报道，NLRP 3炎性体可以独立于转录被激活，这表明引发过程具有未知的必要调控步骤。在这里，我们报告JNK 1介导的NLRP 3在S194处的磷酸化是一个关键的引发事件，并且对于NLRP 3炎性体激活至关重要。我们表明，NLRP 3炎性小体激活在NLRP 3-S194 A敲入小鼠中被破坏。JNK 1介导的NLRP 3 S194磷酸化对于NLRP 3去泛素化至关重要，并促进其自缔合和随后的炎性体组装。重要的是，我们证明了阻断S194磷酸化可以防止cryopyrin-associated periodic syndrome（CAPS）中NLRP 3炎性小体的激活。因此，我们的研究揭示了一个关键的引发分子事件，这是NLRP 3炎性小体激活的先决条件。抑制NLRP 3磷酸化可能是NLRP 3相关疾病的有效治疗方法。
Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.