Toxoplasma histone acetylation remodelers as novel drug targets

Abstract

Toxoplasma gondii is a leading cause of neurological birth defects and a serious opportunistic pathogen. The authors and others have found that Toxoplasma uses a unique nucleosome composition supporting a fine gene regulation together with other factors. Post-translational modifications in histones facilitate the establishment of a global chromatin environment and orchestrate DNA-related biological processes. Histone acetylation is one of the most prominent post-translational modifications influencing gene expression. Histone acetyltransferases and histone deacetylases have been intensively studied as potential drug targets. In particular, histone deacetylase inhibitors have activity against apicomplexan parasites, underscoring their potential as a new class of antiparasitic compounds. In this review, we summarize what is known about Toxoplasma histone acetyltransferases and histone deacetylases, and discuss the inhibitors studied to date. Finally, the authors discuss the distinct possibility that the unique nucleosome composition of Toxoplasma, which harbors a nonconserved H2Bv variant histone, might be targeted in novel therapeutics directed against this parasite.

Figure 1. Human and Toxoplasma H2B family

(A) Sequence alignment of human and Toxoplasma gondii H2Bs. Comparison by multiple alignment (Clustal W). Identical amino acids are denoted by a black shadow and similar amino acids are denoted by gray shadow. (B) N-tail of TgH2Bv and PfH2Bv (Plasmodium falciparum H2B variant, Gene ID: 2655098 PF07_0054). Comparison by multiple alignment (Clustal W). Identical amino acids are denoted by a black shadow and similar amino acids are denoted by gray shadow. Black triangles denote the lysine residues found to be acetylated in P. falciparum, whereas gray triangles denote the lysine residues found to be acetylated in T. gondii. AN: Accession number; HuH2B1: human canonical H2B1 (AN: AAN06695.1); HuH2Bte: Human testis H2B (AN:AAH38109.1); TgH2Ba: Canonical T. gondii H2Ba (Gene ID: TGME49_105160); TgH2Bv: T. gondii H2B variant (AN: AAL01371).

Figure 2. Human and Toxoplasma histone acetylase remodelers

The figure shows examples of the nuclear type A HAT families from human and Toxoplasma. The AN or gene ID are indicated in brackets. Domains of these proteins are illustrated. On the right, there are indicated the lysine position and/or histone that are acetylated by the remodeler. MOZ_SAS domain: MOZ_SAS family, proteins with this region have been suggested to be homologous to acetyltransferases. ?: Unknown; AN: Accession numbers; HAT: Histone acetyltransferase.

Figure 3. Human and Toxoplasma histone deacetylase remodelers

The figure shows examples of the human class I (HDAC1), class II (HDAC9), class III (Sirt6) and class IV (HDAC11) HDACs and Toxoplasma HDACs. The accession numbers or gene ID are indicated between brackets. Domains of these proteins are illustrated. AN: Accession number; ANK: Ankyrin repeats (ankyrin repeats mediate protein–protein interactions in very diverse families of proteins); Gln-rich N-domain: Glutamine-rich N-terminal helical domain of HDAC9. This domain confers responsiveness to calcium signals and mediates interactions with transcription factors and cofactors; HDAC: Histone deacetylase; IPK: Inositol polyphosphate kinase.