title: Improper protein trafficking contributes to artemisinin sensitivity in cells lacking the KDAC Rpd3p.
abstract: 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.
authors.affiliation: Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Amornrat Naranuntarat
authors.initials: AN
authors.lastname: Jensen
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Worathad
authors.initials: W
authors.lastname: Chindaudomsate
authors.affiliation: Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Kanate
authors.initials: K
authors.lastname: Thitiananpakorn
authors.affiliation: Department of Biotechnology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Skorn
authors.initials: S
authors.lastname: Mongkolsuk
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand. Electronic address: laran.jen@mahidol.ac.th.
authors.forename: Laran T
authors.initials: LT
authors.lastname: Jensen
mesh_terms: D037621:Artemisinins / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D006655:Histone Deacetylases / Q000172:deficiency* / Q000235:genetics*; D021381:Protein Transport / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: D037621:Artemisinins; D029701:Saccharomyces cerevisiae Proteins; C031327:artemisinin; C071665:RPD3 protein, S cerevisiae; D006655:Histone Deacetylases
keywords: Artemisinin; Lysine deacetylase; Malaria; Protein trafficking; RPD3; Saccharomyces cerevisiae