| Full text | |
| Author(s): |
Augusto, Leonardo da Silva
[1]
;
Moretti, Nilmar Silvio
[1]
;
Prata Ramos, Thiago Cesar
[1]
;
Leandro de Jesus, Teresa Cristina
[1]
;
Zhang, Min
[2]
;
Castilho, Beatriz A.
[1]
;
Schenkman, Sergio
[1]
Total Authors: 7
|
| Affiliation: | [1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil
[2] NYU, Sch Med, Dept Pathol, New York, NY - USA
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | PLOS PATHOGENS; v. 11, n. 2 FEB 2015. |
| Web of Science Citations: | 13 |
| 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 (eIF2 alpha), 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 eIF2 alpha kinases in protozoan parasites. Here, we characterized an eIF2 alpha 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 eIF2 alpha kinase in T. cruzi. (AU) | |
| FAPESP's process: | 12/50399-4 - Characterization of the protein phosphatase uis2 of Plasmodium as a new tool for malaria drug development |
| Grantee: | Victor Nussenzweig |
| Support Opportunities: | Research Projects - SPEC Program |
| FAPESP's process: | 09/52047-5 - Translational regulation mediated by elF2 in eukaryotes |
| Grantee: | Beatriz Amaral de Castilho |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 11/51973-3 - Cell signaling mechanism of Trypanosoma in response to nutritional alterations and genotoxic agents |
| Grantee: | Sergio Schenkman |
| Support Opportunities: | Research Projects - Thematic Grants |