When pyro(ptosis) meets palm(itoylation)

Pyroptosis, a programmed cell death process, is vital for the immune response against microbial infections and internal danger signals. Recent studies have highlighted the importance of protein palmitoylation, a modification that involves attaching palmitate to cysteine residues, in regulating key proteins involved in pyroptosis. Palmitoylation of cGAS at residue C474 by ZDHHC18 affects its enzymatic activity and DNA binding ability. Similarly, ZDHHC9 promotes cGAS activity through palmitoylation at residues C404/405. NLRP3 palmitoylation at residue C844, mediated by ZDHHC12, impacts its stability and interactions with other proteins, crucial for activating the NLRP3 inflammasome and triggering inflammation. However, the role of ZDHHC5 in NLRP3 palmitoylation remains uncertain due to conflicting findings. Palmitoylation at C88/91 is essential for STING activation and induction of type I interferons. It modulates the formation of multimeric complexes and downstream signaling pathways. GSDMD palmitoylation at C191 is necessary for pore formation and membrane translocation, while GSDME palmitoylation at C407/408 is associated with drug-induced pyroptosis. Moreover, palmitoylation of NOD1 and NOD2 influences their membrane recruitment and immune signaling pathways in response to bacterial peptidoglycans, acting as upstream regulators of pyroptosis. This review summarizes the important roles for palmitoylation in regulating the function of key pyroptosis-related proteins, shedding light on the intricate mechanisms governing immune responses and inflammation.