Longevity & AgingNLRP3 Inflammasome Activation Hinges on a Novel Phase Separation Mechanism
A 2025 Cell Research study reveals that NLRP3 inflammasome activation begins with signal-induced phase separation — a biophysical condensation process — rather than a single molecular trigger. The palmitoyltransferase ZDHHC7 continuously palmitoylates NLRP3 in resting cells, lowering the threshold for phase separation. An intrinsically disordered region (IDR) in NLRP3's FISNA domain, containing three conserved hydrophobic residues, drives multivalent weak interactions enabling condensate formation. Diverse stimuli including potassium efflux, imiquimod, palmitate, and cardiolipin all induce NLRP3 conformational changes that trigger phase separation. Surprisingly, amphiphilic molecules — including common di-alcohols and chemotherapy drugs doxorubicin and paclitaxel — directly reduce NLRP3 solubility to activate it independently of ZDHHC7, revealing an unexpected inflammatory side effect of cancer treatments.
