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Characterization of N-acetyltransferase NAT10 of Leishmania

Grant number: 19/13765-1
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2020
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Nilmar Silvio Moretti
Grantee:Suellen Rodrigues Maran
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Leishmania sp. is the etiological agent of leishmaniasis, a group of diseases that can manifest itself in three main forms: cutaneous, mucocutaneous and visceral. The diversity of the clinical cases presented vary according to the species of Leishmania, being described more than 20 species that can affect the man. During its life cycle Leishmania sp circulates between an invertebrate host and a vertebrate host, and to survive the environmental differences found needs to adapt through changes in the regulation of gene expression, translation and metabolism. The regulation of gene expression in Leishmania occurs mainly post-transcriptionally, through mechanisms of stabilization of mRNAs and regulation of translation. Different post-transcriptional modifications have already been described for mRNAs, such as methylation and pseudouridylation, collectively called epitranscriptome. It has recently been described that mRNAs can be modified by acetylation in mammalian cells, modification previously described only for tRNA and rRNAs, by the activity of N-acetyltransferase NAT10. The acetylation of mRNAs occurs in cytidines and is called N4-acetylcytidine (ac4C), having a great impact in promoting increase in the stability of the mRNAs in general and to promote an increase in the efficiency of the translation. Considering that post-transcriptional regulation is crucial for Leshmania sp., in this project we will study the role of mRNA acetylation in this parasite. Using bioinformatics analyzes we identified the homologous gene of NAT10 in Leishmania mexicana, and using the CRISPR-Cas9 technique we generated single-knockout cell lines, where we replaced one of the copies of the gene, and superexpressors of the NAT10 protein containing a fused fluorescent protein. It was not possible to get knockout parasite, suggesting that this gene is essential for Leishmania. In addition, we determined that the protein has nuclear localization, and that promastigotes single-knockout cell lines have a lower replication rate compared to wild-type cell lines. These preliminary data demonstrate that NAT10 may play an essential role in the posttranscriptional mechanisms of gene expression regulation in Leishmania. Thus, to better understand the role of this protein, we intend in this project: i) to evaluate the role of NAT10 in the acetylation of mRNAs in L. mexicana; ii) to evaluate the role of NAT10 in the processes of growth and differentiation of L. mexicana; iii) investigate the role of NAT10 in the global transcription in L. mexicana; iv) investigate the role of NAT10 in the translation process in L. mexicana; v) to evaluate the anti-leishmanicidal capacity of inhibitors of NAT10. We aim with this project to contribute to a better understanding of an essential mechanism for Leishmania, which opens the prospect of exploring it as a potential target for the development of new drugs for the treatment of this disease of worldwide importance. (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)
MARAN, SUELLEN RODRIGUES; FLECK, KRISTA; MONTEIRO-TELES, NATALIA MELQUIE; ISEBE, TONY; WALRAD, PEGINE; JEFFERS, VICTORIA; CESTARI, IGOR; VASCONCELOS, ELTON J. R.; MORETTI, NILMAR. Protein acetylation in the critical biological processes in protozoan parasites. Trends in Parasitology, v. 37, n. 9, p. 815-830, . (19/13765-1, 18/09948-0)

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