Toxoplasma gondii SIR2A Promotes Tachyzoite Invasion via Lysine Deacetylase Activity

ABSTRACT Accumulating evidence indicates that reversible acetylation modifications are critically involved in the regulation of gene expression, metabolic pathways, and the tachyzoite transformation in Toxoplasma gondii . Silent information regulator 2 (SIR2), an NAD + ‐dependent lysine deacetylase, contributes to the maintenance of specific silent chromatin domains in mammals. However, its exact functions in T. gondii are unclear. In this study, we systematically analyzed two SIR2 homologs, TgSIR2A, and TgSIR2B, in T. gondii . Our findings demonstrate that TgSIR2A exerts a more pronounced effect on tachyzoite growth compared to TgSIR2B. TgSIR2A is predominantly localized in the cytoplasm of tachyzoites and exhibits cell cycle‐dependent expression. Conditional depletion of TgSIR2A significantly impairs tachyzoite invasion. Using gain‐ and loss‐of‐function approaches, we confirmed that the histidine at position 228 is essential for TgSIR2A's catalytic activity. Mutation of this residue elevates global acetylation levels and compromises tachyzoite invasion capacity. Furthermore, acetylated proteomics and interaction analyses suggest that TgSIR2A may regulate gene expression, protein translation, and maturation processes in tachyzoites. Notably, TgBip, an ER‐associated chaperone, may be a substrate of TgSIR2A. Collectively, our results indicate that TgSIR2A plays an important role in tachyzoite invasion via its lysine deacetylase activity, making it a potential target for treating T. gondii infections.