Cell signaling mechanism of Trypanosoma in response to nutritional alterations and genotoxic agents

• Grant number: 11/51973-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2012
• End date: March 31, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Sergio Schenkman
• Grantee: Sergio Schenkman
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant(s): 13/50330-7 - Signaling of Trypanosoma cruzi differentiation in the insect vector, AP.R
• Associated scholarship(s): 14/24338-3 - The stress response by phosphorylation of eIF2alpha, BP.PD; 14/03714-7 - Interaction of Sir2 protein with translation initiation factors in Trypanosoma, BP.PD; 14/01577-2 - The role of eIF2 phosphorylation and sirtuins in the multiplication and differentiation of intracellular Trypanosoma cruzi, BP.DR; 13/02629-3 - Interaction of orthologs of alba, RanBP and other ligants to TOR in Trypanosoma, BP.DR

Abstract

The signaling pathways that control translation initiation/elongation and the transcription and replication arrest after different types of stress in eukaryotes depend on the activation/inactivation of protein kinases. Among them are the kinases that phosphorylate the eukaryotic initiation factor 2 (eIF2), kinases known as TOR, and the phosphorylation of the protein known as eiFSA, characterized as a translation elongation factor. Replication and transcription arrest occurs after histone phosphorylation and RNA polymerase II dephosphorylation followed by chromatin remodeling and DNA repair promoted by single strand DNA-binding proteins and histone chaperones. In this project we intend to identify some of the signaling mechanisms involved in the growth related to the translation control and DNA metabolism after nutritional stresses in protozoan parasites of Trypanosoma species. We will investigate the role of these signaling pathways in the differentiation and growth by detecting alterations in e phosphorylation state and by promoting alterations in the phosphorylation sites. In parallel, we will investigate some components of the chromatin remodeling and the roIe of the differential phosphorylation of the unique carboxy-terminal domain of the large subunit of the RNA Polymerase II in Trypanosoma. These studies will allow us to understand how these parasites deal with environmental changes, which are the basis for their survival in their hosts. This information will be useful to identify new drug targets to treat diseases caused by these types of parasites. (AU)

Scientific publications

(15)

(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, MAY 19 2016. (13/20074-9, 11/51973-3)

LEANDRO DE JESUS, TERESA CRISTINA; NUNES, VINICIUS SANTANA; LOPES, MARIANA DE CAMARGO; MARTIL, DAIANA EVELIN; IWAI, LEO KEI; MORETTI, NILMAR SILVIO; MACHADO, FABRICIO CASTRO; DE LIMA-STEIN, MARIANA L.; THIEMANN, OTAVIO HENRIQUE; ELIAS, MARIA CAROLINA; et al. Chromatin Proteomics Reveals Variable Histone Modifications during the Life Cycle of Trypanosoma cruzi. JOURNAL OF PROTEOME RESEARCH, v. 15, n. 6, p. 2039-2051, JUN 2016. (13/07467-1, 14/03714-7, 08/57910-0, 15/04867-4, 11/06087-5, 11/51973-3, 11/22619-7, 14/01577-2)

AUGUSTO, LEONARDO DA SILVA; MORETTI, NILMAR SILVIO; PRATA RAMOS, THIAGO CESAR; LEANDRO DE JESUS, TERESA CRISTINA; ZHANG, MIN; CASTILHO, BEATRIZ A.; SCHENKMAN, SERGIO. A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi. PLOS PATHOGENS, v. 11, n. 2, FEB 2015. (12/50399-4, 09/52047-5, 11/51973-3)

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, p. 7-pg., 2015-05-01. (13/20074-9, 11/51973-3)

DE OLIVEIRA, VIVIAN CRISTINA; DE LACERDA, MARCELO PITOMBEIRA; MUNIZ MORAES, BARBARA BOMFIM; GOMES, CAIO PEREZ; MARICATO, JULIANA TERZI; SOUZA, OLIVIA FONSECA; SCHENKMAN, SERGIO; PESQUERO, JOAO BOSCO; MORETTI, NILMAR SILVIO; RODRIGUES, CELSO ARRAIS; et al. Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia. Journal of Leukocyte Biology, v. 106, n. 3, SI, p. 581-594, SEP 2019. (11/51973-3, 15/01986-2, 14/27198-8)

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, JAN 2018. (11/51973-3, 15/22031-0, 13/20074-9)

ROUT, MICHAEL P.; OBADO, SAMSON O.; SCHENKMAN, SERGIO; FIELD, MARK C.. Specialising the parasite nucleus: Pores, lamins, chromatin, and diversity. PLOS PATHOGENS, v. 13, n. 3, MAR 2017. (11/51973-3, 15/22031-0)

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, MAY 2015. (13/20074-9, 11/51973-3)

AVILA, CARLA CRISTI D. C.; PEACOCK, LORI; MACHADO, FABRICIO CASTRO; GIBSON, WENDY; SCHENKMAN, SERGIO; CARRINGTON, MARK; CASTILHO, BEATRIZ A.. Phosphorylation of eIF2 alpha on Threonine 169 is not required for Trypanosoma brucei cell cycle arrest during differentiation. Molecular and Biochemical Parasitology, v. 205, n. 1-2, p. 16-21, JAN-FEB 2016. (09/52047-5, 11/51973-3)

COSTA CATTA-PRETA, CAROLINA MOURA; PASCOALINO, BRUNO DOS SANTOS; DE SOUZA, WANDERLEY; MOTTRAM, JEREMY C.; MOTTA, MARIA CRISTINA M.; SCHENKMAN, SERGIO. Reduction of Tubulin Expression in Angomonas deanei by RNAi Modifies the Ultrastructure of the Trypanosomatid Protozoan and Impairs Division of Its Endosymbiotic Bacterium. Journal of Eukaryotic Microbiology, v. 63, n. 6, p. 794-803, NOV-DEC 2016. (11/51973-3)

PRATA RAMOS, THIAGO CESAR; NUNES, VINICIUS SANTANA; NARDELLI, SHEILA CRISTINA; PASCOALINO, BRUNO DOS SANTOS; MORETTI, NILMAR SILVIO; ROCHA, ANTONIO AUGUSTO; AUGUSTO, LEONARDO DA SILVA; SCHENKMAN, SERGIO. Expression of non-acetylatable lysines 10 and 14 of histone H4 impairs transcription and replication in Trypanosoma cruzi. Molecular and Biochemical Parasitology, v. 204, n. 1, p. 1-10, NOV 2015. (11/51973-3)

MORETTI, NILMAR SILVIO; AUGUSTO, LEONARDO DA SILVA; CLEMENTE, TATIANA MORDENTE; PINTO ANTUNES, RAYSA PAES; YOSHIDA, NOBUKO; TORRECILHAS, ANA CLAUDIA; NOGUEIRA CANO, MARIA ISABEL; SCHENKMAN, SERGIO. Characterization of Trypanosoma cruzi Sirtuins as Possible Drug Targets for Chagas Disease. Antimicrobial Agents and Chemotherapy, v. 59, n. 8, p. 4669-4679, AUG 2015. (11/51973-3)

ROCHA, ANTONIO AUGUSTO; MORETTI, NILMAR SILVIO; SCHENKMAN, SERGIO. Stress Induces Changes in the Phosphorylation of Trypanosoma cruzi RNA Polymerase II, Affecting Its Association with Chromatin and RNA Processing. Eukaryotic Cell, v. 13, n. 7, p. 855-865, JUL 2014. (11/51973-3)

PASCOALINO, BRUNO; DINDAR, GUELCIN; VIEIRA-DA-ROCHA, JOAO P.; MACHADO, CARLOS RENATO; JANZEN, CHRISTIAN J.; SCHENKMAN, SERGIO. Characterization of two different Asf1 histone chaperones with distinct cellular localizations and functions in Trypanosoma brucei. Nucleic Acids Research, v. 42, n. 5, p. 2906-2918, MAR 2014. (11/51973-3)

DE LIMA STEIN, MARIANA LEDO; ICIMOTO, MARCELO YUDI; DE CASTRO LEVATTI, ERICA VALADARES; OLIVEIRA, VITOR; STRAUS, ANITA HILDA; SCHENKMAN, SERGIO. Characterization and role of the 3-methylglutaconyl coenzyme A hidratase in Trypanosoma brucei. Molecular and Biochemical Parasitology, v. 214, p. 36-46, JUN 2017. (15/22031-0, 11/51973-3)