The septin modifier, forchlorfenuron, activates NLRP3 via a potassium-independent mitochondrial axis.

Autor:	Holley CL; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: holley@mpiib-berlin.mpg.de., Emming S; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Monteleone MM; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Mellacheruvu M; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Kenney KM; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Lawrence GMEP; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Coombs JR; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Burgener SS; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Schroder K; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: k.schroder@imb.uq.edu.au.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 May 16; Vol. 31 (5), pp. 962-972.e4.
DOI:	10.1016/j.chembiol.2024.04.012
Abstrakt:	The Nod-like receptor protein 3 (NLRP3) inflammasome is activated by stimuli that induce perturbations in cell homeostasis, which commonly converge on cellular potassium efflux. NLRP3 has thus emerged as a sensor for ionic flux. Here, we identify forchlorfenuron (FCF) as an inflammasome activator that triggers NLRP3 signaling independently of potassium efflux. FCF triggers the rearrangement of septins, key cytoskeletal proteins that regulate mitochondrial function. We report that FCF triggered the rearrangement of SEPT2 into tubular aggregates and stimulated SEPT2-independent NLRP3 inflammasome signaling. Similar to imiquimod, FCF induced the collapse of the mitochondrial membrane potential and mitochondrial respiration. FCF thereby joins the imidazoquinolines as a structurally distinct class of molecules that triggers NLRP3 inflammasome signaling independent of potassium efflux, likely by inducing mitochondrial damage. Competing Interests: Declaration of interests K.S. is a co-inventor on patent applications for NLRP3 inhibitors which have been licensed to Inflazome Ltd., a company headquartered in Dublin, Ireland (acquired by Roche). K.S. served on the Scientific Advisory Board of Inflazome and Quench Bio, USA and serves on a Scientific Advisory Board for Novartis, Switzerland. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu