A Study of An essential role for palmitoylation in NLRP3 inflammasome activation.Sihao Zheng et al

The NLRP3 inflammasome is a critical mediator of innate immune response. How NLRP3 responds to stimuli and initiates the assembly of the NLRP3 inflammasome is not fully understood. Here, we found that cellular metabolite, palmitate, facilitates NLRP3 activation by enhancing its S-palmitoylation, in synergy with lipopolysaccharide stimulation. NLRP3 is post-translationally palmitoylated by ZDHHC5 at the leucine-rich repeats (LRR) domain, which promotes NLRP3 inflammasome assembly and activation. Silencing ZDHHC5 blocks NLRP3 oligomerization, NLRP3-NEK7 interaction, and formation of large intracellular ASC aggregates, leading to abrogation in caspase-1 activation and IL-1β release. ABHD17A depalmitoylates NLRP3, and one heritable disease-associated mutation in NLRP3 were found to be associated with defective ABHD17A binding and hyperpalmitoylation. Furthermore, Zdhhc5-/- mice showed defect in NLRP3 inflammasome activation in vivo. Taken together, our data reveal an endogenous mechanism of inflammasome assembly and activation and suggest NLRP3 palmitoylation as a potential target for the treatment of NLRP3 inflammasome-driven diseases.