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

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 alpha subunit of eIF2 (eukaryotic initiation factor-2), a well-characterized event associated with stress remediation in other eukaryotic systems. In addition to characterizing Toxoplasma eIF2alpha (TgIF2alpha), we have discovered a novel eIF2 protein kinase, designated TgIF2K-A (Toxoplasma gondii initiation factor-2kinase). 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 eIF2alpha 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 TgIF2alpha in vitro. Finally, we demonstrate that TgIF2alpha 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.

• Authors: William J Sullivan Jr, Jana Narasimhan, Micah M Bhatti, Ronald C Wek
• Journal: The Biochemical journal (Biochem J) Vol. 380 Issue Pt 2 Pg. 523-31 (Jun 01 2004) ISSN: 1470-8728 [Electronic] England
• PMID: 14989696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Eukaryotic Initiation Factor-2
• Protozoan Proteins
• eukaryotic initiation factor-2 alpha, Toxoplasma gondii
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• initiation factor-2 kinase, Toxoplasma gondii
• Peptide Synthases

Topics

• Amino Acid Sequence (genetics)
• Animals
• Cloning, Molecular (methods)
• Eukaryotic Initiation Factor-2 (chemistry, genetics, physiology)
• Metamorphosis, Biological (genetics, physiology)
• Molecular Sequence Data
• Peptide Synthases (physiology)
• Phosphorylation
• Protein Biosynthesis (physiology)
• Protein Serine-Threonine Kinases (chemistry, genetics, physiology)
• Protozoan Proteins (chemistry, physiology)
• Sequence Alignment (methods)
• Species Specificity
• Toxoplasma (enzymology, growth & development, pathogenicity)
• eIF-2 Kinase (chemistry, genetics, physiology)