NLRP3炎性体激活,细胞因子分泌和焦亡对不同刺激的反应至关重要,与各种疾病密切相关。在刺激时,NLRP3经历亚细胞膜运输和构象重排,在微管组织中心(MTOC)为炎症小体组装做准备。这里,我们使用人类和鼠细胞阐明了这些有序过程的协调机制。具体来说,NLRP3通过棕榈酰转移酶zDHHC1在两个位点进行棕榈酰化,促进其在亚细胞膜之间的运输,包括线粒体,跨高尔基网络(TGN),和内体。这种动态贩运最终导致NLRP3本地化为MTOC,其中LATS1/2,在启动期间预先招募到MTOC,磷酸化NLRP3以进一步促进其与NIMA相关激酶7(NEK7)的相互作用,最终导致NLRP3完全激活。始终如一,Zdhhc1缺乏减轻了LPS诱导的炎症,并在小鼠中提供了针对死亡的保护。总之,我们的发现为NLRP3膜运输和炎症体激活的调节提供了有价值的见解,由棕榈酰化和磷酸化事件控制。
NLRP3 inflammasome activation, essential for cytokine secretion and pyroptosis in response to diverse stimuli, is closely associated with various diseases. Upon stimulation, NLRP3 undergoes subcellular membrane trafficking and conformational rearrangements, preparing itself for inflammasome assembly at the microtubule-organizing center (MTOC). Here, we elucidate an orchestrated mechanism underlying these ordered processes using human and murine cells. Specifically, NLRP3 undergoes palmitoylation at two sites by palmitoyl transferase zDHHC1, facilitating its trafficking between subcellular membranes, including the mitochondria, trans-Golgi network (TGN), and endosome. This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. Consistently, Zdhhc1-deficiency mitigated LPS-induced inflammation and conferred protection against mortality in mice. Altogether, our findings provide valuable insights into the regulation of NLRP3 membrane trafficking and inflammasome activation, governed by palmitoylation and phosphorylation events.