Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2
Year: 2021
Type: article
Abstract: Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.
Source: Cell Reports
Authors: Martin Marek, Elizabeth Ramos-Morales, Gisele F.A. Picchi-Constante, Theresa Bayer, Carina Norström, Daniel Herp, Policarpo A. Sales-Junior, Eloise P. Guerra-Slompo, Kristin Hausmann, Alokta Chakrabarti, Tajith B. Shaik, Annika Merz, Edouard Troesch, Karin Schmidtkunz, Samuel Goldenberg, Raymond J. Pierce, Marina M. Mourão, Manfred Jung, Johan Schultz, Wolfgang Sippl, Nilson I.T. Zanchin, Christophe Romier
Institutions: Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, Instituto Carlos Chagas, Martin Luther University Halle-Wittenberg, Kancera (Sweden), University of Freiburg, Fiocruz Minas, Fundação Oswaldo Cruz, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, Center for Infection and Immunity of Lille
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,853
OpenAlex ID: W4200433816