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

SMYD3 dimethylates gasdermin D at lysine 43, promoting caspase cleavage, oligomerization, and membrane localization of GSDMD-NT to induce pyroptosis.

• Why it matters: Pyroptosis and inflammation must be tightly regulated after inflammasome activation, yet the mechanisms controlling GSDMD activity are not fully defined.
• What they did: The study identifies SMYD3 as a GSDMD-interacting lysine methyltransferase that catalyzes dimethylation at lysine 43, then tests SMYD3 disruption or inhibition.
• The result: Disrupting or inhibiting SMYD3 alleviates overactivated inflammation and protects against lipopolysaccharide-induced death in mice and zebrafish, supporting a new regulatory mechanism for GSDMD-mediated pyroptosis.