Mapping the reactive cysteine landscape of the NOD-like receptor pyrin domain-containing 3 protein

Cysteines C150, C196, and C884 in NLRP3 are consistently detected as ROS-reactive targets, and mutating C150/C196 or C933/C941 reduces IL-1b output in a reconstituted inflammasome assay.

• Why it matters: ROS dependence in NLRP3 activation is established, but which cysteine residues are directly modified and how that relates to NLRP3 conformational and activity changes is unclear.
• What they did: The study used affinity-capture of NLRP3 followed by reverse-thiol trapping, chemoproteomics, in vitro and in cellulo validation, and molecular dynamics/structural modeling of cysteine sulfenylation in the LRR.
• The result: C150A and C196A (NACHT) and C933A and C941A (LRR) reduced IL-1b output, while simulations suggest LRR sulfenylation can reposition the trLRR loop to destabilize inactive NLRP3.

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