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On Friday, February 24, 2023,听Nilmar Moretti, PhD, Assistant Professor in the Department of Microbiology, Immunology and Parasitology at the Federal University of Sao Paulo, Brazil, will be giving a talk entitled "Modifying to adapt: the impact of protein acetylation in Leishmania differentiation鈥�. This joint special seminar is cohosted by the 91社区 Research Centre on Complex Traits (MRCCT), the Department of Microbiology and Immunology and the Dahdaleh Institute of Genomic Medicine.

• Time: 11:00 am
• Date: February 24, 2023
• Location: McIntyre Building, Karp Amphitheater -听Room 501

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Abstract:

鈥淧rotein acetylation has been implicated in the regulation of essential cellular processes in diverse prokaryotes and eukaryotes, including protozoan parasites. Previous proteomic analysis from our group revealed differential protein acetylation among the three main Leishmania mexicana stages (procyclic, metacyclic and amastigote), suggesting a central role for this modification during parasite differentiation. Lysine acetylation is regulated by lysine acetyltransferases (KATs), which add acetyl groups to lysines, and lysine deacetylases (KDACs) that remove the acetyl groups. To better understand the role of protein acetylation in the Leishmania stage differentiation we characterized the four zinc-dependent lysine deacetylases (DAC1, 3, 4 and 5) and found that DAC1 and 3 are essential for the parasite, while DAC4 and 5 are dispensable. Moreover, DAC1 and 5 are cytosolic and DAC3 and 4 are nuclear, suggesting distinct function of these enzymes. Phenotype screening assays using the mutant parasites demonstrated that DAC1, 3 and 5 are involved in procyclic multiplication, while DAC1 and 5 gene knockout impairs differentiation from procyclic to infective metacyclics in vitro. Experimental in vivo infection of Lutzomyia longipalpis further confirmed the importance of DAC5 for parasite differentiation by revealing impaired metacyclogenesis. In addition, we found that the absence of DAC5 significantly affects procyclic differentiation to axenic amastigotes and vice versa, which might be related to morphological alterations observed during time-course differentiation experiments. Finally, we evaluated the impact of DACs in the progression of host infection in vitro and in vivo. We found a significant reduction in intracellular amastigote multiplication of DAC5 null mutants in vitro compared to the parental cell line. A similar scenario was observed in the mouse in vivo infection assays for DAC5 mutants, with no apparent lesion development compared to parental parasites. Altogether, these results suggest that regulation of protein acetylation levels is important for Leishmania stage differentiation, opening the opportunity to explore DACs as potential drug targets and to obtain live attenuated vaccinal strain in a near future鈥�