北京大学蒋争凡团队的一项最新研究发现了信号诱导的NLRP3相分离启动炎性小体激活。相关论文于2025年4月1日发表在《细胞研究》杂志上。

本文报道了信号依赖性NLRP3相分离启动其激活，其中棕榈酰转移酶ZDHHC7介导的补补性NLRP3棕榈酰化和NLRP3 FISNA结构域的IDR区域发挥了重要作用。

此外，IDR中三个保守的疏水残基介导多价弱相互作用。激活NLRP3的刺激，包括K⁺外排和NLRP3相互作用分子咪喹莫特、棕榈酸酯和心磷脂，都能改变NLRP3的构象，并在细胞和/或体外诱导其相分离和激活。令人惊讶的是，以抑制生物分子相分离为目的的双醇类两亲性分子和化疗药物阿霉素和紫杉醇，通过直接诱导NLRP3相分离而独立于ZDHHC7激活NLRP3。机制上，两亲性分子降低了棕榈酰化和非棕榈酰化NLRP3的溶解度，直接诱导其相分离和激活，而棕榈酰化在一定程度上降低了NLRP3的溶解度，但没有激活。因此，静息细胞中zdhhc7介导的NLRP3棕榈酰化通过降低NLRP3相分离的阈值来激活NLRP3，以响应任何不同的刺激，而NLRP3溶解性降低分子如二醇和化疗药物直接激活NLRP3。信号诱导的NLRP3相分离可能为NLRP3激活提供了最简单、最直接的机制基础。

据悉，NLRP3炎性小体可被多种刺激激活，包括感染、细胞内和环境刺激物。NLRP3如何感知这些不相关的刺激以及是什么激活了NLRP3仍然未知。

附：英文原文

Title: Signal-induced NLRP3 phase separation initiates inflammasome activation

Author: Zou, Gonglu, Tang, Yuluan, Yang, Jie, Fu, Shuo, Li, Yuheng, Ren, Xuanyao, Zhou, Nanhai, Zhao, Wenlong, Gao, Juyi, Ruan, Ziran, Jiang, Zhengfan

Issue&Volume: 2025-04-01

Abstract: NLRP3 inflammasome is activated by diverse stimuli including infections, intracellular and environmental irritants. How NLRP3 senses these unrelated stimuli and what activates NLRP3 remain unknown. Here we report that signal-dependent NLRP3 phase separation initiated its activation, in which the palmitoyltransferase ZDHHC7-mediated tonic NLRP3 palmitoylation and an IDR region in the FISNA domain of NLRP3 play important roles. Moreover, three conserved hydrophobic residues in the IDR critically mediate multivalent weak interactions. NLRP3-activating stimuli including K+ efflux and NLRP3-interacting molecules imiquimod, palmitate, and cardiolipin all cause NLRP3 conformational change and induce its phase separation and activation in cells and/or in vitro. Surprisingly, amphiphilic molecules like di-alcohols used to inhibit biomolecular phase separation and chemotherapeutic drugs doxorubicin and paclitaxel activate NLRP3 independently of ZDHHC7 by directly inducing NLRP3 phase separation. Mechanistically, amphiphilic molecules decrease the solubility of both palmitoylated and non-palmitoylated NLRP3 to directly induce its phase separation and activation while NLRP3 palmitoylation reduces its solubility to some extent without activation. Therefore, ZDHHC7-mediated NLRP3 palmitoylation in resting cells licenses its activation by lowering the threshold for NLRP3 phase separation in response to any of the diverse stimuli whereas NLRP3 solubility-reducing molecules like di-alcohols and chemotherapeutic drugs activate NLRP3 directly. The signal-induced NLRP3 phase separation likely provides the simplest and most direct mechanistic basis for NLRP3 activation.

DOI: 10.1038/s41422-025-01096-6

Source: https://www.nature.com/articles/s41422-025-01096-6