Improper protein trafficking contributes to artemisinin sensitivity in cells lacking the KDAC Rpd3p

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 sit4 Delta mutants with impaired endoplasmic reticulum (ER) to Golgi protein trafficking. Decreased accumulation of the transporters Pdr5p, Fur4p, and Tat2p was observed in rpd3 Delta and sit4 Delta cells. The unfolded protein response is induced in rpd3 Delta 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. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.