Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii

Jana Narasimhan, Bradley R. Joyce, Arunasalam Naguleswaran, Aaron T. Smith, Meredith R. Livingston, Stacy E. Dixon, Isabelle Coppens, Ronald Wek, William Sullivan

Research output: Contribution to journalArticle

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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-2α (TgIF2α) is phosphorylated during stress and establish that protozoan parasites utilize translation control to modulate gene expression during development. Importantly, TgIF2α 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) eIF2α 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.

Original languageEnglish
Pages (from-to)16591-16601
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number24
DOIs
StatePublished - Jun 13 2008

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Eukaryotic Initiation Factor-2
Toxoplasma
Cysts
Phosphotransferases
Apicomplexa
Unfolded Protein Response
Phosphorylation
Endoplasmic Reticulum Stress
Protein Biosynthesis
Eukaryotic Cells
Eukaryota
Gene expression
Endoplasmic Reticulum
Parasites
Proteins
Gene Expression
Recurrence
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii. / Narasimhan, Jana; Joyce, Bradley R.; Naguleswaran, Arunasalam; Smith, Aaron T.; Livingston, Meredith R.; Dixon, Stacy E.; Coppens, Isabelle; Wek, Ronald; Sullivan, William.

In: Journal of Biological Chemistry, Vol. 283, No. 24, 13.06.2008, p. 16591-16601.

Research output: Contribution to journalArticle

Narasimhan, Jana ; Joyce, Bradley R. ; Naguleswaran, Arunasalam ; Smith, Aaron T. ; Livingston, Meredith R. ; Dixon, Stacy E. ; Coppens, Isabelle ; Wek, Ronald ; Sullivan, William. / Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 24. pp. 16591-16601.
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