TY - JOUR TI - Endosomal trafficking of two-pore K+ efflux channel TWIK2 to plasmalemma mediates NLRP3 inflammasome activation and inflammatory injury AU - Huang, Long Shuang AU - Anas, Mohammad AU - Xu, Jingsong AU - Zhou, Bisheng AU - Toth, Peter T AU - Krishnan, Yamuna AU - Di, Anke AU - Malik, Asrar B A2 - Vanaja, Sivapriya A2 - Rothlin, Carla V VL - 12 PY - 2023 DA - 2023/05/09 SP - e83842 C1 - eLife 2023;12:e83842 DO - 10.7554/eLife.83842 UR - https://doi.org/10.7554/eLife.83842 AB - 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. KW - ATP KW - Rab11a KW - P2X7 KW - caspase 1 KW - exocytosis KW - calcium JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -