ArticlePLoS pathogens2015
A membrane-bound eIF2 alpha kinase located in endosomes is regulated by heme and controls differentiation and ROS levels in Trypanosoma cruzi.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 45 citations in OpenAlex.
- Advances and challenges in the search for new treatments for Chagas disease.Memorias do Instituto Oswaldo Cruz · 2026Review
- The integrated stress response in apicomplexan and trypanosomatid parasites: balancing survival and pathogenesis.Frontiers in immunology · 2026Review
- Transcriptomic response to different heme sources inMicrobial cell (Graz, Austria) · 2026Article
- Rational Design of Natural Xanthones Against Gram-negative Bacteria.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Metacyclogenesis as the Starting Point of Chagas Disease.International journal of molecular sciences · 2023Review
- Article
- The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy.Frontiers in cellular and infection microbiology · 2022Review
- The Use of Antioxidants as Potential Co-Adjuvants to Treat Chronic Chagas Disease.Antioxidants (Basel, Switzerland) · 2021Review
- Characterization and functional analysis of the proteins Prohibitin 1 and 2 in Trypanosoma cruzi.PLoS neglected tropical diseases · 2021Article
- Article
- GCN2-Like Kinase Modulates Stress Granule Formation During Nutritional Stress inFrontiers in cellular and infection microbiology · 2020Article
- Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host.Oxidative medicine and cellular longevity · 2020Review
- Bioactive lipids regulate Trypanosoma cruzi development.Parasitology research · 2019Article
- Translational repression by an RNA-binding protein promotes differentiation to infective forms in Trypanosoma cruzi.PLoS pathogens · 2018Article
- Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.Scientific reports · 2018Article
- Translational Control in the Latency of Apicomplexan Parasites.Trends in parasitology · 2017Review
- Identification of novel targets for multiple myeloma through integrative approach with Monte Carlo cross-validation analysis.Journal of bone oncology · 2017Article
- Quantitative proteome and phosphoproteome analyses highlight the adherent population during Trypanosoma cruzi metacyclogenesis.Scientific reports · 2017Article
- TheThe Journal of biological chemistry · 2017Article
- Nuclear Compartmentalization Contributes to Stage-Specific Gene Expression Control inFrontiers in cell and developmental biology · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Translation initiation has been described as a key step for the control of growth and differentiation of several protozoan parasites in response to environmental changes. This occurs by the activation of protein kinases that phosphorylate the alpha subunit of the translation initiation factor 2 (eIF2α), which decreases translation, and in higher eukaryotes favors the expression of stress remedial response genes. However, very little is known about the signals that activate eIF2α kinases in protozoan parasites. Here, we characterized an eIF2α kinase of Trypanosoma cruzi (TcK2), the agent of Chagas' disease, as a transmembrane protein located in organelles that accumulate nutrients in proliferating parasite forms. We found that heme binds specifically to the catalytic domain of the kinase, inhibiting its activity. In the absence of heme, TcK2 is activated, arresting cell growth and inducing differentiation of proliferative into infective and non-proliferative forms. Parasites lacking TcK2 lose this differentiation capacity and heme is not stored in reserve organelles, remaining in the cytosol. TcK2 null cells display growth deficiencies, accumulating hydrogen peroxide that drives the generation of reactive oxygen species. The augmented level of hydrogen peroxide occurs as a consequence of increased superoxide dismutase activity and decreased peroxide activity. These phenotypes could be reverted by the re-expression of the wild type but not of a TcK2 dead mutant. These findings indicate that heme is a key factor for the growth control and differentiation through regulation of an unusual type of eIF2α kinase in T. cruzi.
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