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J. Biol. Chem., Vol. 283, Issue 24, 16591-16601, June 13, 2008

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Translation Regulation by Eukaryotic Initiation Factor-2 Kinases in the Development of Latent Cysts in Toxoplasma gondii^*

Jana Narasimhan¹, Bradley R. Joyce¹, Arunasalam Naguleswaran, Aaron T. Smith, Meredith R. Livingston, Stacy E. Dixon, Isabelle Coppens^¶, Ronald C. Wek, and William J. Sullivan, Jr.²

From the Department of Pharmacology and Toxicology and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and ^¶Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205

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 (TgIF2) is phosphorylated during stress and establish that protozoan parasites utilize translation control to modulate gene expression during development. Importantly, TgIF2 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) eIF2 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.

Received for publication, January 25, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01GM49164 and R01GM64350 (to R. C. W.). This study was also supported in part by American Heart Association Grant 0750201Z (to W. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 635 Barnhill Dr., MS A-525, Indianapolis, IN 46202. Fax: 317-274-7714; E-mail: wjsulliv{at}iupui.edu.

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