Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.
Fiche publication
Date publication
décembre 2021
Journal
Cell reports
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
Marek M, Ramos-Morales E, Picchi-Constante GFA, Bayer T, Norström C, Herp D, Sales-Junior PA, Guerra-Slompo EP, Hausmann K, Chakrabarti A, Shaik TB, Merz A, Troesch E, Schmidtkunz K, Goldenberg S, Pierce RJ, Mourão MM, Jung M, Schultz J, Sippl W, Zanchin NIT, Romier C
Lien Pubmed
Résumé
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.
Mots clés
Trypanosoma cruzi, atypical three-dimensional structure, chemical inhibition, eukaryotic parasites, functional essentiality, histone deacetylases
Référence
Cell Rep. 2021 Dec 21;37(12):110129