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A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi

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 (eIF...

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Autores principales: da Silva Augusto, Leonardo, Moretti, Nilmar Silvio, Ramos, Thiago Cesar Prata, de Jesus, Teresa Cristina Leandro, Zhang, Min, Castilho, Beatriz A., Schenkman, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450062/
https://www.ncbi.nlm.nih.gov/pubmed/25658109
http://dx.doi.org/10.1371/journal.ppat.1004618
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author da Silva Augusto, Leonardo
Moretti, Nilmar Silvio
Ramos, Thiago Cesar Prata
de Jesus, Teresa Cristina Leandro
Zhang, Min
Castilho, Beatriz A.
Schenkman, Sergio
author_facet da Silva Augusto, Leonardo
Moretti, Nilmar Silvio
Ramos, Thiago Cesar Prata
de Jesus, Teresa Cristina Leandro
Zhang, Min
Castilho, Beatriz A.
Schenkman, Sergio
author_sort da Silva Augusto, Leonardo
collection PubMed
description 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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spelling pubmed-44500622015-06-23 A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi da Silva Augusto, Leonardo Moretti, Nilmar Silvio Ramos, Thiago Cesar Prata de Jesus, Teresa Cristina Leandro Zhang, Min Castilho, Beatriz A. Schenkman, Sergio PLoS Pathog Research Article 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. Public Library of Science 2015-02-06 /pmc/articles/PMC4450062/ /pubmed/25658109 http://dx.doi.org/10.1371/journal.ppat.1004618 Text en © 2015 da Silva Augusto et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
da Silva Augusto, Leonardo
Moretti, Nilmar Silvio
Ramos, Thiago Cesar Prata
de Jesus, Teresa Cristina Leandro
Zhang, Min
Castilho, Beatriz A.
Schenkman, Sergio
A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title_full A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title_fullStr A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title_full_unstemmed A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title_short A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi
title_sort membrane-bound eif2 alpha kinase located in endosomes is regulated by heme and controls differentiation and ros levels in trypanosoma cruzi
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450062/
https://www.ncbi.nlm.nih.gov/pubmed/25658109
http://dx.doi.org/10.1371/journal.ppat.1004618
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