Endosomal trafficking of two-pore K + efflux channel TWIK2 to plasmalemma mediates NLRP3 inflammasome activation and inflammatory injury

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...

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Published in:eLife 2023-05, Vol.12
Main Authors: Huang, Long Shuang, Anas, Mohammad, Xu, Jingsong, Zhou, Bisheng, Toth, Peter T, Krishnan, Yamuna, Di, Anke, Malik, Asrar B
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Adoptive transfer
Animals
ATP
Biological Transport
calcium
caspase 1
Caspase 1 - metabolism
Cell activation
Cell Biology
Cell surface
exocytosis
Homeostasis
Inflammasomes
Inflammasomes - metabolism
Inflammation
Interleukin-1beta - metabolism
Localization
Lungs
Macrophages
Macrophages - metabolism
Mice
Microscopy
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
P2X7
Plasma
Plasma membranes
Plasmids
Potassium
Potassium channels
Proteins
Rab11a
Therapeutic targets
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.83842