Endosomal trafficking of two pore K+ efflux channel TWIK2 to plasmalemma mediates NLRP3 inflammasome activation and inflammatory injury
- Shanghai Jiao Tong University, China
- University of Illinois at Chicago, United States
- University of Chicago, United States
- The University of Illinois at Chicago, United States
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript. Source Data have been provided for Figure 3, Figure 4, Figure 5, and Figure 6 for the Western blots.
Article and author information
Author details
Funding
National Institutes of Health (P01-HL60678)
- Asrar B Malik
National Institutes of Health (P01-HL077806)
- Asrar B Malik
National Institutes of Health (R01-HL118068)
- Asrar B Malik
National Institutes of Health (R01-HL90152)
- Asrar B Malik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were housed in the University of Illinois Animal Care Facility in accordance with institutional and NIH guidelines. Veterinary care and animal experiments were approved by the University of Illinois Animal Care & Use Committee (ACC protocol number: 21-032).
Copyright
© 2023, Huang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Endosomal trafficking of two pore K+ efflux channel TWIK2 to plasmalemma mediates NLRP3 inflammasome activation and inflammatory injury
eLife 12:e83842.
https://doi.org/10.7554/eLife.83842
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