S-Palmitoylation regulates signaling mediated by NLRP3 and other innate immune receptors

The innate immune system coordinates the immediate response to microbial pathogens and tissue damage to allow pathogen clearance and tissue repair. Pathogen recognition receptors (PRRs) recognize danger- and pathogen-associated molecular patterns to trigger immune signaling. The PRR NLRP3 is activated by inflammatory stimuli to instigate the formation of the NLRP3-associated inflammasome. Emerging data highlight the importance of S-palmitoylation (or S-acylation) for NLRP3 activation. Several protein acyltransferases promote NLRP3 S-palmitoylation at a distinct set of cysteine residues to regulate assembly and intracellular localization of the NLRP3 inflammasome. S-Palmitoylation of gasdermin D (GSDMD) and other mediators of innate immunity, including NOD2, Toll-like receptors (TLRs), and stimulator of interferon gene (STING), also modulates immune responses and inflammatory cell death. However, the physiological implication of these S-palmitoylation events has not been established yet, and S-palmitoylation can have a negative effect on inflammatory signaling as well. This review outlines the key features of S-palmitoylation in innate immune signaling and highlights the unresolved questions.