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Lysine deacetylases (KDACs) inhibitors may have therapeutic value in anti-malarial combination therapies with artemisinin. To evaluate connections between KDACs and artemisinin, Saccharomyces cerevisiae deletion mutants in KDAC genes were assayed. Deletion of RPD3, but not other KDAC genes, resulted in strong sensitivity to artemisinin, which was also observed in sit4Δ mutants with impaired endoplasmic reticulum (ER) to Golgi protein trafficking. Decreased accumulation of the transporters Pdr5p, Fur4p, and Tat2p was observed in rpd3Δ and sit4Δ cells. The unfolded protein response is induced in rpd3Δ cells consistent with retention of proteins in the ER. Disruption of protein trafficking appears to sensitize cells to artemisinin and targeting these pathways may be useful as part of artemisinin based anti-malarial therapy.

A gene named phd1+ encoding a protein highly homologous to the yeast and human histone deacetylases, such as Saccharomyces cerevisiae Rpd3p and human HDAC1, was cloned from Schizosaccharomyces pombe. The immune complex isolated from S. pombe cells expressing Phd1 fused to the FLAG epitope showed histone deacetylase activity, which was inhibited by trichostatin A (TSA), a specific inhibitor of histone deacetylase. The null mutation of phd1+ resulted in a marked decrease in the total cellular histone deacetylase activity and an increase in the sensitivity to TSA. Although the phd1 disruptant showed no obvious defect in the mitotic cell cycle or mating, both homothallic haploid and heterothallic diploid cells failed to form spores in the absence of phd1+. These results indicate that phd1+ encodes a histone deacetylase, which is involved in the meiotic cell cycle in S. pombe.