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Global analysis of protein acetylation in Trypanosoma cruzi

Grant number: 13/20074-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): January 10, 2014
Effective date (End): October 31, 2014
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Sergio Schenkman
Grantee:Nilmar Silvio Moretti
Supervisor abroad: Kenneth D. Stuart
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Seattle Biomedical Research Institute (Seattle BioMed), United States  


Lysine acetylation has emerged as a major post-translational modification involved in diverse cellular functions in higher eukaryotes. While histone proteins are the founding members of lysine acetylation substrates, it is now clear that hundreds of other proteins can be acetylated in multiple compartments of the cell. During its life cycle the Trypanosoma cruzi face different environment conditions, which requires diverse metabolic changes to its survival that could involve changes in the global protein acetylation levels. To address this question we first analyzed protein acetylation during the parasite transition from non-infective to infective forms (metacyclogenesis) and found differences in acetylation of several proteins. Also, some modifications were observed during transition from exponential to stationary phase of parasite, but in a more accentuated level. These preliminary results suggest the importance of protein acetylation in the regulation of crucial mechanisms in T. cruzi. The acetylation/deacetylation process is regulated through the activities of two families of proteins, lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Amongst the KDACs we have the Sirtuins, NAD+-dependent histone deacetylases involved in different functional mechanisms, such as gene silencing, DNA damage repair, ageing and metabolic process. T. cruzi has two genes that encodes to sirtuin proteins, called TcSir2rp1 and TcSir2rp3. To investigate if these proteins play a role in the control of protein acetylation levels, we generated cell lines overexpressing tagged version of TcSir2rp1 and TcSir2rp3. Initially we demonstrated that TcSir2rp1 is a cytosolic protein while TcSir2rp3 is a mitochondrial. Moreover, overexpression of both TcSir2 proteins reduced the acetylation levels of specific proteins, as measured by immunoblotting with antibodies against acetyl-lysine. TcSir2rp3 overexpression leads to an increase in the resistance to oxidative stress and a reduction in the reactive oxygen species (ROS) production when compared with wild-type parasites. Interesting, an increase in the rate of metacyclogenesis was observed in the TcSir2rp3 cell lines, indicating a role of this protein in the control of metabolic process of the parasite. The same was not observed in TcSir2rp1 parasites, which has impairment in both cell growth and differentiation to metacyclic forms. Altogether, these data provide evidence that protein acetylation could be relevant for functional adaption mechanisms in the parasite upon environmental changes and sirtuins might be central in these phenomena. In this project we will perform a global protein analysis to identify the main proteins that are targets for acetylation/deacetylation machinery and could be involved in the metabolic changes triggered during the parasite differentiation. Also, we will analyze the sirtuins targets to better understand the role of these proteins in the control of global protein acetylation levels in T. cruzi. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CESTARI, IGOR; HAAS, PAIGE; MORETTI, NILMAR SILVIO; SCHENKMAN, SERGIO; STUART, KEN. Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites. Cell Chemical Biology, v. 23, n. 5, p. 608-617, . (13/20074-9, 11/51973-3)
MORETTI, NILMAR SILVIO; CESTARI, IGOR; ANUPAMA, ATASHI; STUART, KEN; SCHENKMAN, SERGIO. Comparative Proteomic Analysis of Lysine Acetylation in Trypanosomes. JOURNAL OF PROTEOME RESEARCH, v. 17, n. 1, p. 374-385, . (11/51973-3, 15/22031-0, 13/20074-9)
PHAN, ISABELLE Q. H.; DAVIES, DOUGLAS R.; MORETTI, NILMAR SILVIO; SHANMUGAM, DHANASEKARAN; CESTARI, IGOR; ANUPAMA, ATASHI; FAIRMAN, JAMES W.; EDWARDS, THOMAS E.; STUART, KENNETH; SCHENKMAN, SERGIO; et al. Iron superoxide dismutases in eukaryotic pathogens: new insights from Apicomplexa and Trypanosoma structures. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 71, n. 5, SI, p. 615-621, . (13/20074-9, 11/51973-3)

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