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Background Histone deacetylase 8 from Schistosoma mansoni (SmHDAC8) is essential to parasite growth and development within the mammalian host and is under investigation as a target for the development of selective inhibitors as novel schistosomicidal drugs. Although some protein substrates and protein partners of human HDAC8 have been characterized, notably indicating a role in the function of the cohesin complex, nothing is known of the partners and biological function of SmHDAC8. Methodology/Principal findings We therefore employed two strategies to characterize the SmHDAC8 interactome. We first used SmHDAC8 as a bait protein in yeast two-hybrid (Y2H) screening of an S. mansoni cDNA library. This allowed the identification of 49 different sequences encoding proteins. We next performed co-immunoprecipitation (Co-IP) experiments on parasite extracts with an anti-SmHDAC8 antibody. Mass spectrometry (MS) analysis allowed the identification of 160 different proteins. Conclusions/Significance SmHDAC8 partners are involved in about 40 different processes, included expected functions such as the cohesin complex, cytoskeleton organization, transcriptional and translational regulation, metabolism, DNA repair, the cell cycle, protein dephosphorylation, proteolysis, protein transport, but also some proteasome and ribosome components were detected. Our results show that SmHDAC8 is a versatile deacetylase, potentially involved in both cytosolic and nuclear processes., Author summary Using a target-based strategy to develop new drugs for the treatment of schistosomiasis we had earlier identified Schistosoma mansoni histone deacetylase 8 (SmHDAC8) as essential for parasite development and survival in the mammalian host. Selective inhibitors of this enzyme show promise as lead compounds for drug development. However, the biological role of SmHDAC8 has not been established. We identified the potential partner proteins and the processes in which it is involved by combining two methods: yeast two-hybrid screening and co-immunoprecipitation with mass spectrometry. These approaches yielded complementary sets of potential partner proteins that are actors in about 40 different cellular processes. These include known roles for the human counterpart of SmHDAC8, like interactions with the cohesin complex and the cytoskeleton, as well as novel interactions such as with proteasomes and ribosomal proteins. Our results emphasize the implication of SmHDAC8 in both nuclear and cytosolic processes and the versatility of this enzyme, suggesting why it is vital to the parasite and a promising drug target.

Only one drug is currently available for the treatment and control of schistosomiasis and the increasing risk of selecting strains of schistosome that are resistant to praziquantel means that the development of new drugs is urgent. With this objective we have chosen to target the enzymes modifying histones and in particular the histone acetyltransferases and histone deacetylases (HDAC). Inhibitors of HDACs (HDACi) are under intense study as potential anti-cancer drugs and act via the induction of cell cycle arrest and/or apoptosis. Schistosomes like other parasites can be considered as similar to tumours in that they maintain an intense metabolic activity and rate of cell division that is outside the control of the host. We have shown that HDACi can induce apoptosis and death of schistosomes maintained in culture and have set up a consortium (Schistosome Epigenetics: Targets, Regulation, New Drugs) funded by the European Commission with the aim of developing inhibitors specific for schistosome histone modifying enzymes as novel lead compounds for drug development.