Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASC^C171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

中文翻译：

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ASC 去谷胱甘肽是 NLRP3 炎症小体激活的检查点


NLRP3 炎性体的激活受到精确控制，以避免过度激活。尽管已经揭示了调节 NLRP3 炎症小体激活的多个分子，但控制 NLRP3 炎症小体激活的检查点仍然难以捉摸。在这里，我们发现 NLRP3 炎症小体的激活是由巨噬细胞中 GSTO1 促进的 ASC 去谷胱甘肽化控制的。 ASC 的谷胱甘肽化会抑制 ASC 寡聚化，从而抑制巨噬细胞中 NLRP3 炎症小体的激活，除非 GSTO1 在线粒体 ROS 和三酰甘油合成的控制下结合 ASC 并在内质网对 ASC 进行去谷胱甘肽化。在表达 ASC ^C171A （一种没有谷胱甘肽化位点的突变 ASC）的巨噬细胞中，NLRP3 炎症小体的激活不依赖于 GSTO1、ROS 且较少依赖于信号 2。此外， AscC171A小鼠体内表现出 NLRP3 依赖性过度炎症。我们的结果表明，ASC 的谷胱甘肽化抑制 NLRP3 炎症小体激活，而 GSTO1 促进的 ASC 在代谢控制下的 ER 去谷胱甘肽化是激活 NLRP3 炎症小体的检查点。