SMYD3-catalyzed dimethylation of gasdermin D at lysine 43 promotes pyroptosis and inflammatory responses

Gasdermin D (GSDMD), a key pyroptosis effector downstream of inflammasome activation, undergoes precise regulation by multiple posttranslational modifications. Here, we identify SMYD3, a lysine methyltransferase, as a positive regulator of GSDMD. SMYD3 interacts with GSDMD and catalyzes its dimethylation at lysine 43. This modification promotes GSDMD cleavage by caspases, leading to increased oligomerization and membrane localization of GSDMD N-terminal fragment (GSDMD-NT), which ultimately induces pyroptosis. Disrupting or inhibiting SMYD3 alleviates overactivated inflammation, thereby protecting against lipopolysaccharide-induced death in mice and zebrafish. Our findings reveal a role for SMYD3 in regulating the inflammatory response and shed light on a new mechanism that modulates GSDMD-mediated pyroptosis.