Regulating the trans-regulators: investigating the PRMT7 molecular pathway as an epigenetic regulator of Leishmania virulence

• Grant number: 15/13618-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2016
• End date: July 31, 2019
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: MRC, UKRI ; Newton Fund, with FAPESP as a partner institution in Brazil
• Principal Investigator: Angela Kaysel Cruz
• Grantee: Angela Kaysel Cruz
• Principal researcher abroad: Pegine Walrad
• Institution abroad: University of York, England
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Michael John Plevin
• Associated scholarship(s): 17/14765-0 - Comparative computational analysis of Leishmania knockout transfectant for PRMT7: transcriptome and methylproteome, BP.TT; 16/14657-0 - Methylation mediated by PRMT7 on the differentiation process of promastigotes into amastigotes and the parasite Leishmania major virulence, BP.PD

Abstract

Species of Leishmania threaten 350 million people worldwide on four continents. New treatments and vaccines are desperately needed and the UK and Brazilian governments are committed to the World Health Organization’s recent call to further support Neglected Tropical Disease research. The single-cell Leishmania parasite differentiates in distinct forms during its lifecycle to adapt to different hosts; moving from mammals to sandflies and back to mammals by sandfly bites. Major changes to the parasite's morphology, metabolism and virulence proteins occur during these transitions that enable them to survive. Leishmania gene expression relies almost exclusively upon mRNA regulation. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the adaptation of these parasites enable them to survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. We have recently isolated a major control panel "Regulator" protein, PRMT7, which controls Leishmania parasite virulence in mammalian infections. Very few Leishmania regulator proteins have yet been identified and this finding represents a major leap forward to isolate and examine this regulatory pathway and interfering with parasite virulence. To study the PRMT7 regulation pathway and identify the way this protein functions, we have assembled a team of experts in Leishmania parasite PRMT proteins, RNA regulators and protein interactions. We believe insight into this pathway may help to understand some parasite resources to successfully establish human infections. We have identified some downstream target proteins of PRMT7 and now seek to determine if they are regulated by PRMT7 and whether they participate in Leishmania parasite virulence. These Leishmania proteins are different from human proteins; therefore we can use these differences to target Leishmania- specific virulence factors, block their function and block Leishmaniasis from developing. Significant findings may provide insight to Leishmaniasis research. We propose to find more regulators of Leishmania virulence using the PRMT7 virulence pathway. We will identify how these regulators function, and test whether any are essential for parasite survival. The novelty and importance of our project is four fold: 1. PRMT7 is the only Protein aRginine Methyl Transferase enzyme that has been characterized in Leishmania parasites thus far and we demonstrated an inverse correlation between the protein level and virulence (Ferreira et al., 2014). 2. Methylation as a protein modification is uncharacterised in Leishmania spp. parasites. 3. Regulatory RNA binding proteins (RBPs) that are important in parasite lifecycle differentiation, human infectivity and virulence are largely unknown in Leishmania. 4. The 3-dimensional molecular structures of RBPs and mRNA: protein complexes are largely unknown in all parasites and are absent in Leishmania. (AU)

Scientific publications

(5)

(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)

CAMPAGNARO, GUSTAVO D.; NAY, EDWARD; PLEVIN, MICHAEL J.; CRUZ, ANGELA K.; WALRAD, PEGINE B.. Arginine Methyltransferases as Regulators of RNA-Binding Protein Activities in Pathogenic Kinetoplastids. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 8, JUN 11 2021. (18/14398-0, 20/02372-6, 15/13618-8)

LORENZON, LUCAS; QUILLES JR, JOSE C.; CAMPAGNARO, GUSTAVO DANIEL; ORSINE, LISSUR AZEVEDO; ALMEIDA, LETICIA; VERAS, FLAVIO; MISERANI MAGALHAES, RUBENS DANIEL; DINIZ, JULIANA ALCOFORADO; FERREIRA, TIAGO RODRIGUES; CRUZ, ANGELA KAYSEL. Functional Study of Leishmania braziliensis Protein Arginine Methyltransferases (PRMTs) Reveals That PRMT1 and PRMT5 Are Required for Macrophage Infection. ACS INFECTIOUS DISEASES, v. 8, n. 3, p. 17-pg., 2022-03-11. (21/10043-5, 20/00088-9, 16/00969-0, 16/14657-0, 15/13618-8, 18/14398-0, 20/02372-6, 19/18607-5)

CAMPAGNARO, GUSTAVO DANIEL; LORENZON, LUCAS BIGOLIN; RODRIGUES, MATEUS AUGUSTO; DEFINA, TANIA PAULA AQUINO; PINZAN, CAMILA FIGUEIREDO; FERREIRA, TIAGO RODRIGUES; CRUZ, ANGELA KAYSEL. Overexpression of Leishmania major protein arginine methyltransferase 6 reduces parasite infectivity in vivo. Acta Tropica, v. 244, p. 7-pg., 2023-06-01. (15/13618-8, 14/00220-3, 18/14398-0, 13/13237-9, 20/02372-6, 10/01129-9)

FERREIRA, TIAGO R.; DOWLE, ADAM A.; PARRY, EWAN; ALVES-FERREIRA, ELIZA V. C.; HOGG, KAREN; KOLOKOUSI, FOTEINI; LARSON, TONY R.; PLEVIN, MICHAEL J.; CRUZ, ANGELA K.; WALRAD, PEGINE B.. PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites. Nucleic Acids Research, v. 48, n. 10, p. 5511-5526, JUN 4 2020. (15/13618-8, 14/19400-1, 14/50954-3)

DINIZ, JULIANA ALCOFORADO; CHAVES, MARIANA M.; VASELEK, SLAVICA; MISERANI MAGALHAES, RUBENS D.; RICCI-AZEVEDO, RAFAEL; DE CARVALHO, RENAN V. H.; LORENZON, LUCAS B.; FERREIRA, TIAGO R.; ZAMBONI, DARIO; WALRAD, PEGINE B.; et al. Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model. PLoS Neglected Tropical Diseases, v. 15, n. 3, MAR 2021. (19/18607-5, 16/14657-0, 18/02761-2, 17/02998-0, 15/13618-8, 16/00969-0)