Vicki Jeffers, Ph.D
Toxoplasma gondii, a prevalent, intracellular parasite, must rapidly adapt to fluctuating nutrient environments during its life cycle to survive and cause disease. This study focuses on AP2X-7, an essential DNA-binding transcription factor in Toxoplasma that is dynamically regulated by post-translational modifications (PTMs), particularly lysine acetylation and proteolytic cleavage. AP2X-7 is constitutively transcribed but only detectable as full-length protein during the G1 phase of the cell cycle. Notably, acetylation of AP2X-7 is highly responsive to cytoplasmic acetyl-CoA levels, a key metabolic indicator. This suggests acetylation directly modulates AP2X-7’s DNA-binding activity and function. The protein’s acetylation is reduced under low acetyl-CoA conditions, and mutation of a critical lysine residue (K1785) impairs parasite growth, underscoring its functional importance.
The study proposes two aims:
- to map PTMs on AP2X-7 under different environmental conditions (intracellular vs. extracellular)
- to determine the distinct roles of N-terminal and Cterminal cleavage products using N-terminal tagging and inducible degradation. These findings will reveal how PTMs and cleavage act as a molecular rheostat to fine-tune AP2X-7 activity during acute and chronic infection. Given the lack of effective treatments for chronic toxoplasmosis, understanding these regulatory mechanisms may uncover novel therapeutic targets for this globally prevalent, incurable disease.
The parasite Toxoplasma gondii infects approximately 60 million Americans with an incurable chronic infection that presents a serious risk to pregnant women, their unborn babies, and immunocompromised people. We have identified a parasite protein called AP2X-7, that is critical for parasite survival during infection but its essential function is unknown. The goal of this project is to understand the function of this factor in the parasite, to support the development of effective new treatments for toxoplasmosis.
