Title:

Multi-layer Regulation of the Essential ApiAP2 Factor AP2X-7 in Toxoplasma gondii

Toxoplasma gondii must rapidly adapt to diverse host environments through coordinated transcriptional remodeling. How environmental signals regulate transcription remains unclear. ApiAP2 transcription factors are the primary transcriptional regulators in Toxoplasma, but how these proteins respond to metabolic and environmental signals is largely unknown. Here we propose TgAP2X-7, an essential ApiAP2 factor, as a candidate bridge between environmental state and transcriptional control. Epitope tagging shows AP2X-7 localizes to the nucleus and is restricted to the G1 phase despite having constitutively expressed transcript. Conditional depletion of AP2X-7 blocks progression through the parasite lytic cycle, with pronounced defects in invasion and replication. RNA-seq analysis further shows that AP2X-7 loss causes global transcriptional dysregulation, with upregulated genes enriched for microtubule-associated process and downregulated genes biased towards the apical complex. We identified stable C-terminal proteolytic cleavage products of AP2X-7 that vary across parasite states, including intracellular vs extracellular conditions, suggesting regulated processing linked to environmental context. Additionally, AP2X-7 is post-translationally modified by acetylation and lactylation. Acetylation decreases under low acetyl-CoA conditions, suggesting it to function as a link of nutrient environment to transcriptome. Mutation of a key acetylation site (K1785R) produces a significant growth defect and alters cleavage patterns, indicating functional interplay between acetylation and proteolytic processing. These findings support a model in which AP2X-7 integrates metabolic and environmental signals through post-translational modifications and proteolysis to regulate transcriptional programs essential for parasite survival. This work establishes AP2X-7 as a critical regulator of adaptive gene expression in T. gondii and a potential target for therapeutic intervention.

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