Parasite-specific eIF2 (eukaryotic initiation factor-2) kinase required for stress-induced translation control

William J. Sullivan, Jana Narasimhan, Micah M. Bhatti, Ronald C. Wek

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The ubiquitous intracellular parasite Toxoplasma gondii (phylum Apicomplexa) differentiates into an encysted form (bradyzoite) that can repeatedly re-emerge as a life-threatening acute infection (tachyzoite) upon impairment of immunity. Since the switch from tachyzoite to bradyzoite is a stress-induced response, we sought to identify components related to the phosphorylation of the α subunit of eIF2 (eukaryotic initiation factor-2), a well-characterized event associated with stress remediation in other eukaryotic systems. In addition to characterizing Toxoplasma eIF2α (TgIF2α), we have discovered a novel eIF2 protein kinase, designated TgIF2K-A (Toxoplasma gondii initiation factor-2 kinase). Although the catalytic domain of TgIF2K-A contains sequence and structural features that are conserved among members of the eIF2 kinase family, TgIF2K-A has an extended N-terminal region that is highly divergent from other eIF2 kinases. TgIF2K-A specifically phosphorylates the regulatory serine residue of yeast eIF2α in vitro and in vivo, and can modulate translation when expressed in the yeast model system. We also demonstrate that TgIF2K-A phosphorylates the analogous regulatory serine residue of recombinant TgIF2α in vitro. Finally, we demonstrate that TgIF2α phosphorylation in tachyzoites is enhanced in response to heat shock or alkaline stress, conditions known to induce parasite differentiation in vitro. Collectively, this study suggests that eIF2 kinase-mediated stress responses are conserved in Apicomplexa, and a novel family member exists that may control parasite-specific events, including the clinically relevant conversion into bradyzoite cysts.

Original languageEnglish (US)
Pages (from-to)523-531
Number of pages9
JournalBiochemical Journal
Volume380
Issue number2
DOIs
StatePublished - Jun 1 2004

Keywords

  • Apicomplexa
  • Eukaryotic initiation factor-2 (eIF2)
  • Stress
  • Toxoplasma
  • Transcription
  • Translation

ASJC Scopus subject areas

  • Biochemistry

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