Indiana University-Purdue University Indianapolis (IUPUI) / The obligate intracellular protozoan parasite Toxoplasma gondii is a medically relevant pathogen that has infected a third of the world’s population. Toxoplasma is the causative agent of toxoplasmosis, which can have severe repercussions such as encephalitis and even death in immunocompromised patients. Current treatments for toxoplasmosis only target acute infection and can be toxic to patients, resulting in complications including allergy and bone marrow suppression. Thus, the identification of novel drug targets and therapies for toxoplasmosis is vital. Epigenetic modulators of lysine acetylation, including ‘writers,’ ‘erasers,’ and ‘readers,’ have been identified as promising drug targets for protozoan parasites. The lysine acetyltransferase (KAT) GCN5b appears to be an essential gene for Toxoplasma viability. The KAT domain of GCN5b is essential to GCN5b function and is targetable by small molecule inhibitors. While the acetyltransferase activity of this gene is well-characterized, the functionality of its C-terminal bromodomain (BRD) remains to be understood. Bromodomains are readers of lysine acetylation, and recently, bromodomain inhibitors have shown promise in a number of human diseases, as well as in protozoan parasites. We hypothesized that the GCN5b bromodomain is critical for Toxoplasma viability. The data reported herein suggest that the GCN5b bromodomain is important for tachyzoite viability and may serve as a novel therapeutic target in Toxoplasma.

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Indiana University-Purdue University Indianapolis (IUPUI) / Toxoplasma gondii, a single-celled eukaryotic pathogen, has infected one-third of the world’s population and is the causative agent of toxoplasmosis. The disease primarily affects immunocompromised individuals such as AIDS, cancer, and transplant patients. The parasites can infect any nucleated cell in warm-blooded vertebrates, but because they preferentially target CNS, heart, and ocular tissue, manifestations of infection often include encephalitis, myocarditis, and a host of neurological and ocular disorders. Toxoplasma can also be transmitted congenitally by a mother who becomes infected for the first time during pregnancy, which may result in spontaneous abortion or birth defects in the child. Unfortunately, the therapy currently available for treating toxoplasmosis exhibits serious side effects and can cause severe allergic reactions. Therefore, there is a desperate need to identify novel drug targets for developing more effective, less toxic treatments. The regulation of proteins via lysine acetylation, a reversible post-translational modification, has previously been validated as a promising avenue for drug development. Lysine acetyltransferases (KATs) are responsible for the acetylation of hundreds of proteins throughout prokaryotic and eukaryotic cells. In Toxoplasma, we identified a KAT that exhibits homology to Elongator protein 3 (TgElp3), the catalytic component of a transcriptional elongation complex. TgElp3 contains the highly conserved radical S-adenosylmethionine and KAT domains but also possesses a unique C-terminal transmembrane domain (TMD). Interestingly, we found that the TMD anchors TgElp3 in the outer mitochondrial membrane (OMM) such that the catalytic domains are oriented towards the cytosol. Our results uncovered the first tail-anchored mitochondrial KAT reported for any species to date. We also discovered a shortened form of Elp3 present in mouse mitochondria, suggesting that Elp3 functions beyond transcriptional elongation across eukaryotes. Furthermore, we established that TgElp3 is essential for parasite viability and that its OMM localization is important for its function, highlighting its value as a potential target for future drug development.