An apicomplexan ankyrin-repeat histone deacetylase with relatives in photosynthetic eukaryotes

Abstract

Cryptosporidium parvum is a member of the Apicomplexa that lacks a plastid and associated nuclear-encoded genes, which has hampered its use in evolutionary comparisons with algae and eliminated a pool of potentially useful drug targets. Here we show that apicomplexan parasites possess an unusual family of class II histone deacetylase (HDAC) proteins with orthologues that are present in other chromalveolates and primitive algae. A striking feature of these HDAC proteins is the presence of ankyrin repeats in the amino-terminus that appear to be required for enzyme activity. In vitro and in vivo analyses of the C. parvum orthologue indicate that this subclass of chromatin-remodelling proteins is targeted by the anti-cancer drug suberoylanilide hydroxamic acid and that these proteins are most likely involved in the essential process of H4 histone deacetylation that coincides with DNA replication. We propose that members of this novel class of histone deacetylase can serve as promising new targets for treatments against debilitating diseases such as cryptosporidosis, toxoplasmosis and malaria.

Nullscript inhibits Cryptosporidium and Toxoplasma growth

“…Histone deacetylases (HDACs) are very important in the regulation of transcription and maintenance of cells in organisms. Three HDACs have been identified in C. parvum ( Rider and Zhu, 2009 ). The HDACi vorinostat (SAHA) was reported to inhibit the deacetylation activity of CpHDAC3 in C. parvum ( Guo et al, 2018 ).…”

Effects of curcumin on Cryptosporidium parvum in vitro

“…Histone deacetylase regulates transcription and is one of the novel therapeutic targets for fungal-derived antiprotozoal agents (like acipidin), thereby such drugs may alter proliferation of apicomplexan parasites such as C. parvum (Darkin-Rattray et al 1996). A new member of the apicomlexan histone deacetylase family has been recently described in C. parvum (Rider and Zhu 2009), and it seems to be possible that a respective mechanism is involved in inhibition of growth of Cryptosporidium by curcumin. Curcumin at lower doses of 1 to 15 µM scavenges ROS or slightly increases ROS level, but at higher doses (20 to 50 µM) induces oxidative stress (especially H 2 O 2 ) in cancer cells (Cao et al 2006) and malarial parasites (Cui et al 2007).…”

The role of chromatin in Plasmodium gene expression

“…A class I HDAC has been characterized as a nuclear protein (Joshi et al ., 1999) and the Cryptosporidium parvum orthologue of a P. falciparum class II HDAC has some specificity for H4K8ac and H4K12ac (Rider and Zhu, 2009). P. falciparum has two paralogues of the class III HDAC Sir2 which both maintain heterochromatin and mutually exclusive var gene expression by silencing different groups of var genes (Duraisingh et al ., 2005; Freitas‐Junior et al ., 2005; Tonkin et al ., 2009).…”