title: Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii.
abstract: A key problem in the treatment of numerous pathogenic eukaryotes centers on their development into latent forms during stress. For example, the opportunistic protist Toxoplasma gondii converts to latent cysts (bradyzoites) responsible for recrudescence of disease. We report that Toxoplasma eukaryotic initiation factor-2alpha (TgIF2alpha) is phosphorylated during stress and establish that protozoan parasites utilize translation control to modulate gene expression during development. Importantly, TgIF2alpha remains phosphorylated in bradyzoites, explaining how these cells maintain their quiescent state. Furthermore, we have characterized novel eIF2 kinases; one in the endoplasmic reticulum and a likely regulator of the unfolded protein response (TgIF2K-A) and another that is a probable responder to cytoplasmic stresses (TgIF2K-B). Significantly, our data suggest that 1) the regulation of protein translation through eIF2 kinases is associated with development, 2) eIF2alpha phosphorylation is employed by cells to maintain a latent state, and 3) endoplasmic reticulum and cytoplasmic stress responses evolved in eukaryotic cells before the early diverging Apicomplexa. Given its importance to pathogenesis, eIF2 kinase-mediated stress responses may provide opportunities for novel therapeutics.
authors.affiliation: Department of Pharmacology and Toxicology and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Narasimhan
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Joyce
authors.forename: Arunasalam
authors.initials: A
authors.lastname: Naguleswaran
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Smith
authors.forename: Meredith R
authors.initials: MR
authors.lastname: Livingston
authors.forename: Stacy E
authors.initials: SE
authors.lastname: Dixon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.forename: William J
authors.initials: WJ
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D002499:Centrifugation, Density Gradient; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018384:Oxidative Stress; D010766:Phosphorylation; D014176:Protein Biosynthesis; D014122:Toxoplasma / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D014415:Tunicamycin; D019892:eIF-2 Kinase