The role of cysteines and S-palmitoylation in NLRP3 inflammasome activation

Abstract

Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) is a cytosolic pattern recognition receptor with a critical role in numerous autoinflammatory disorders and non-communicable diseases characterized by chronic inflammation. In innate immune cells, such as macrophages, NLRP3 assembles into a multimolecular complex known as inflammasome, in response to intracellular homeostatic disturbances caused by tissue damage or infection. Activation of the NLRP3 inflammasome triggers a pro-inflammatory signaling cascade, culminating in pyroptosis – a lytic, inflammatory form of cell death – and the release of the cytokine interleukin-1β. Despite extensive research, the molecular mechanisms governing NLRP3 activation remain incompletely understood. In this study, I identified a pivotal role for cysteine residues in NLRP3 activation. Mechanistically, we demonstrated that a few residues undergo S-palmitoylation, a reversible lipid modification involving the attachment of a long-chain fatty acid. This modification enhances protein membrane association and stability, thereby facilitating NLRP3 trafficking to organelles, promoting inflammasome assembly and sustaining cytokine release. Moreover, I identified the palmitoyltransferase ZDHHC7 as a critical enzyme required for activation. <br/> These findings establish S-palmitoylation as a key post-translational regulatory mechanism of NLRP3, providing new insights into inflammasome activation and uncovering potential therapeutic targets for inflammation-associated diseases.