Publication: Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming
Authors
Martín Sánchez, María Rosario Fátima ; Pelegrín Vivancos, Pablo ; Green, Jack Peter ; Yu, Shi ; Lopez-Castejon, Gloria ; Lawrence, Catherine B. ; Brough, David
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Publisher
National Academy of Sciences
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DOI
https://doi.org/10.1073/pnas.1812744115
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info:eu-repo/semantics/article
Description
Abstract
The NLRP3 inflammasome is an important regulator of inflammation and immunity. It is a multi-molecular platform formed within cells that facilitates the activation of pro-inflammatory caspases to drive secretion of cytokines such as IL-1β. Knowledge of the mechanisms regulating formation of the NLRP3-inflammasome is incomplete. Here we report Cl- channel dependent formation of dynamic ASC oligomers and inflammasome specks that remain inactive in the absence of K+ efflux. Formed after Cl- efflux exclusively ASC specks are NLRP3 dependent, reversible, and inactive, though they further prime inflammatory responses accelerating and enhancing release of IL-1β in response to a K+ efflux inducing stimulus. NEK7 is a specific K+ sensor and does not associate with NLRP3 under conditions stimulating exclusively Cl- efflux, but does after K+ efflux, activating the complex driving inflammation. Our investigation delivers new mechanistic understanding into inflammasome activation and the regulation of inflammatory responses.
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Citation
Green, J., Yu, S., Martín-Sánchez, F., Pelegrin, P., Lopez-Castejon, G., Lawrence, C. B., & Brough, D. (2018). Chloride regulates dynamic NLRP3-dependent ASC oligomerisation and inflammasome priming. Proceedings of the National Academy of Sciences, 115(40), E9371-E9380. https://doi.org/10.1073/pnas.1812744115
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