Palmitoylation promotes chaperone-mediated autophagic degradation of NLRP3 to modulate inflammation.

The critical intracellular pattern recognition receptor NLRP3 senses pathogenic organisms and endogenous danger signals via forming inflammasomes to orchestrate innate immune responses. Dysfunction of NLRP3 inflammasomes is implicated in several inflammatory disorders. Hence, it is important to uncover the mechanisms preventing sustained NLRP3 inflammasome activation. Recently, we revealed that ZDHHC12-mediated palmitoylation enhances NLRP3 degradation through the chaperone-mediated autophagy pathway, and identified gain-of-function variants of NLRP3 in autoinflammatory diseases, which induce excessive NLRP3 inflammasome activation through decreased NLRP3 palmitoylation level and impaired chaperone-mediated autophagic degradation of NLRP3.