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The stress response by phosphorylation of eIF2alpha

Grant number: 14/24338-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2015
Effective date (End): June 30, 2016
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Sergio Schenkman
Grantee:Leonardo da Silva Augusto
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:11/51973-3 - Cell signaling mechanism of Trypanosoma in response to nutritional alterations and genotoxic agents, AP.TEM

Abstract

The acquisition of iron in free form or in the form of heme is a key step in the process of multiplication and survival of Trypanosoma cruzi, the protozoan that causes Chagas disease. T. cruzi is not able to synthesize heme and there is evidence that forms the parasite that proliferate in the cytosol of infected cells, or gut of the insect vector acquire heme through specific transporters (Cupello et al., 2011). Furthermore, the availability of heme in the host affects the progression of Chagas' disease (Paiva et al., 2012). We characterize a protein kinase (TcK2) that regulates the initiation of translation through the phosphorylation of the eukaryotic initiation factor eIF2± translation. We found that in the absence of heme protein kinase that is activated causing phosphorylation of eIF2a, decreased transcription and differentiation of the parasite infective forms. The TcK2 is in the endosomal membrane organelles that accumulate inside heme (e-Silva-Cunha et al., 2006; Figueiredo et al., 2004). We show that in knouckout parasites of TcK2, heme is accumulated in the cytosol of the parasite. At the same time we have evidence that changes in phosphorylation sites of eIF2a affect survival after addition of oxidative agents. These organelles should be well heme carriers, whose activity and / or expression may be modulated by phosphorylation and activation of TcK2 eIF2a. In fact, heme carriers located in endosomal membranes were identified in Leishmania sp, and the like genes are present in T. cruzi. Thus, in this project we intend to a) verify that the phosphorylation of eIF2a affects the expression or activity of heme transporters and the same occurs for enzymes involved in oxidative stress response. (AU)

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