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

• Published in: Cell chemical biology Vol. 31; no. 5; pp. 962 - 972.e4
• Main Authors: Holley, Caroline L, Emming, Stefan, Monteleone, Mercedes M, Mellacheruvu, Manasa, Kenney, Kirsten M, Lawrence, Grace M E P, Coombs, Jared R, Burgener, Sabrina S, Schroder, Kate
• Format: Journal Article
• Language: English
• Published: United States 16.05.2024
• Subjects: Animals; Humans; Inflammasomes - metabolism; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phenylurea Compounds - chemistry; Phenylurea Compounds - pharmacology; Potassium - metabolism; Pyridines - chemistry; Pyridines - pharmacology; Septins - metabolism; Signal Transduction - drug effects; NLRP3; forchlorfenuron; macrophage; septin; inflammation; inflammasome
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2024.04.012

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.