Department of Pharmacology and Regenerative Medicine, The University of Illinois College of Medicine, Chicago, United States.
Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
Elife. 2023 May 9;12:e83842. doi: 10.7554/eLife.83842.
Potassium efflux via the two-pore K channel TWIK2 is a requisite step for the activation of NLRP3 inflammasome, however, it remains unclear how K efflux is activated in response to select cues. Here, we report that during homeostasis, TWIK2 resides in endosomal compartments. TWIK2 is transported by endosomal fusion to the plasmalemma in response to increased extracellular ATP resulting in the extrusion of K. We showed that ATP-induced endosomal TWIK2 plasmalemma translocation is regulated by Rab11a. Deleting Rab11a or ATP-ligated purinergic receptor P2X7 each prevented endosomal fusion with the plasmalemma and K efflux as well as NLRP3 inflammasome activation in macrophages. Adoptive transfer of Rab11a-depleted macrophages into mouse lungs prevented NLRP3 inflammasome activation and inflammatory lung injury. We conclude that Rab11a-mediated endosomal trafficking in macrophages thus regulates TWIK2 localization and activity at the cell surface and the downstream activation of the NLRP3 inflammasome. Results show that endosomal trafficking of TWIK2 to the plasmalemma is a potential therapeutic target in acute or chronic inflammatory states.
钾通过双孔钾通道 TWIK2 外流是 NLRP3 炎性体激活的必要步骤，然而，对于钾外流如何响应特定信号而被激活仍不清楚。在这里，我们报告在稳态条件下，TWIK2 位于内体隔室中。TWIK2 通过内体融合被运送到质膜，以响应细胞外 ATP 的增加，从而导致钾的外排。我们表明，ATP 诱导的内体 TWIK2 质膜易位受 Rab11a 调节。删除 Rab11a 或与 ATP 连接的嘌呤能受体 P2X7 都可防止内体与质膜融合以及巨噬细胞中钾外流和 NLRP3 炎性体激活。将耗尽 Rab11a 的巨噬细胞过继转移到小鼠肺部可防止 NLRP3 炎性体激活和炎症性肺损伤。我们得出结论，Rab11a 介导的巨噬细胞内体运输因此调节 TWIK2 在细胞表面的定位和活性，以及 NLRP3 炎性体的下游激活。结果表明，TWIK2 向质膜的内体运输是急性或慢性炎症状态的潜在治疗靶点。
