J Biol Chem. 2008 Apr 16 [Epub ahead of print]
Translation regulation by eIF2 kinases in the development of latent cysts in Toxoplasma gondii
Narasimhan J, Joyce BR, Naguleswaran A, Smith AT, Livingston MR, Dixon SE, Coppens I, Wek RC, Sullivan WJ Jr.
Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202.
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-2 alpha (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. Further, we have characterized novel eIF2 kinases: one in the endoplasmic reticulum (ER) 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) ER and cytoplasmic stress responses evolved in eukaryotic cells prior to the early-diverging Apicomplexa. Given its importance to pathogenesis, eIF2 kinase-mediated stress responses may provide opportunities for novel therapeutics.
PMID: 18420584 [PubMed - as supplied by publisher]