Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cell Rep. 2024 Sep 24;43(9):114688. doi: 10.1016/j.celrep.2024.114688. Epub 2024 Aug 27.
The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity is not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for the pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent-crosslinking-based mechanism, promoting inter- and intraprotein MICA (methyl imidazole crosslink between cysteine and arginine) posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.
NLRP3 炎性小体在疾病中促进炎症，但其活性调节的完整机制尚未完全阐明。在已确定的调节机制中，NLRP3 的共价修饰已成为该蛋白药理学失活的常见途径。在这里，我们表明，糖酵解酶磷酸甘油酸激酶 1（PGK1）的抑制导致甲基乙二醛的积累，这是一种反应性代谢物，其水平增加会减少细胞中 NLRP3 的组装和炎症信号转导。我们发现，甲基乙二醛通过非酶促、基于共价交联的机制使 NLRP3 失活，促进 NLRP3 内 MICA（半胱氨酸和精氨酸之间的甲基咪唑交联）的翻译后交联。这项工作确立了 NLRP3 能够感知一系列亲电化学物质，包括外源性小分子和内源性反应性代谢物，并提出了一种糖酵解通量可以调节中央炎症信号通路激活状态的机制。
