Glycosomal bromodomain factor 1 from Trypanosoma cruzi enhances trypomastigote cell infection and intracellular amastigote growth

Abstract

Acetylation is a ubiquitous protein modification present in prokaryotic and eukaryotic cells that participates in the regulation of many cellular processes. The bromodomain is the only domain known to bind acetylated lysine residues. In the last few years, many bromodomain inhibitors have been developed in order to treat diseases caused by aberrant acetylation of lysine residues and have been tested as anti-parasitic drugs. In the present paper, we report the first characterization of Trypanosoma cruzi bromodomain factor 1 (TcBDF1). TcBDF1 is expressed in all life cycle stages, but it is developmentally regulated. It localizes in the glycosomes directed by a PTS2 (peroxisome-targeting signal 2) sequence. The overexpression of wild-type TcBDF1 is detrimental for epimastigotes, but it enhances the infectivity rate of trypomastigotes and the replication of amastigotes. On the other hand, the overexpression of a mutated version of TcBDF1 has no effect on epimastigotes, but it does negatively affect trypomastigotes' infection and amastigotes' replication.

Comparative Metabolism of Free‐living Bodo saltans and Parasitic Trypanosomatids

“…Another protein very recently identified in Trypanosoma spp., bromodomain factor 1 (BDF1), is directed to glycosomes by its PTS2 (Ritagliati et al. ). Bromodomain‐containing proteins bind acetylated lysines in histones and other proteins regulating gene expression (Siegel et al.…”

Overexpression of bromodomain factor 3 in Trypanosoma cruzi (TcBDF3) affects differentiation of the parasite and protects it against bromodomain inhibitors

“…There is no evidence available yet about the interaction of these bromodomains with the inhibitors. However, we recently showed that a mutated version of Tc BDF1 that has no effect on epimastigote growth negatively affects trypomastigote infection and amastigote replication . These results demonstrate that bromodomain factors have different roles during T. cruzi’ s life cycle.…”

“…However, their effect on the parasite cannot be exclusively attributed to Tc BDF3 because at least three other bromodomain‐containing proteins are present in T. cruzi . Among them, we have characterized the nuclear Tc BDF2 and recently Tc BDF1 . Tc BDF2 is a classic histone‐binding bromodomain and Tc BDF1 is a glycosomal protein that has an important role in infection and amastigote duplication.…”

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

“…Microscopy and cellular fractionation confirmed that TcBDF1 localizes to the parasite glycosome, a peroxisome-like organelle that is unique to kinetoplastids and required for biochemical processes related to glucose metabolism (89). Although the exact function and associated factors of TcBDF1 remain unknown, its importance for parasite viability was indicated by studies demonstrating that overexpression of the protein in epimastigotes led to growth arrest and parasite death (90). A mutant version of TcBDF1 had no effect on epimastigote growth but negatively impacted trypomastigote infection and amastigote replication (90).…”

“…Although the exact function and associated factors of TcBDF1 remain unknown, its importance for parasite viability was indicated by studies demonstrating that overexpression of the protein in epimastigotes led to growth arrest and parasite death (90). A mutant version of TcBDF1 had no effect on epimastigote growth but negatively impacted trypomastigote infection and amastigote replication (90). How these phenotypes relate to the localization of TcBDF1 at glycosomes, or the ability of the protein to bind acetylated lysines, remains to be elucidated.…”