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EIF2α phosphorylation is regulated in intracellular amastigotes for the generation of infective Trypanosoma cruzi trypomastigote forms.
Cell Microbiol. 2020 Jun 29 [Online ahead of print]CM

Abstract

Trypanosomatids regulate gene expression mainly at the post-transcriptional level through processing, exporting and stabilising mRNA and control of translation. In most eukaryotes, protein synthesis is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2) at serine 51. Phosphorylation halts overall translation by decreasing availability of initiator tRNAmet to form translating ribosomes. In trypanosomatids, the N-terminus of eIF2α is extended with threonine 169 the homologous phosphorylated residue. Here, we evaluated whether eIF2α phosphorylation varies during the Trypanosoma cruzi life cycle, the etiological agent of Chagas' disease. Total levels of eIF2α are diminished in infective and non-replicative trypomastigotes compared with proliferative forms from the intestine of the insect vector or amastigotes from mammalian cells, consistent with decreased protein synthesis reported in infective forms. eIF2α phosphorylation increases in proliferative intracellular forms prior to differentiation into trypomastigotes. Parasites overexpressing eIF2αT169A or with an endogenous CRISPR/Cas9-generated eIF2αT169A mutation were created and analysis revealed alterations to the proteome, largely unrelated to the presence of μORF in epimastigotes. eIF2αT169A mutant parasites produced fewer trypomastigotes with lower infectivity than wild type, with increased levels of sialylated mucins and oligomannose glycoproteins, and decreased galactofuranose epitopes and the surface protease GP63 on the cell surface. We conclude that eIF2α expression and phosphorylation levels affect proteins relevant for intracellular progression of T. cruzi.

Authors+Show Affiliations

Departmento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.Departmento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.Departmento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.Departmento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.Department of Genomics, Instituto de Investigaciones Biológicas Clemente Estable, Ministerio de Educación y Cultura, Montevideo, Uruguay. Laboratory of Molecular Interactions, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.Department of Genomics, Instituto de Investigaciones Biológicas Clemente Estable, Ministerio de Educación y Cultura, Montevideo, Uruguay. Laboratory of Molecular Interactions, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.Drug Discovery and Evaluation, Centre for Research of Pathogenicity and Virulence of Parasites, Charles University, Prague, Czech Republic.Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, UK. Institute of Parasitology, Czech Academy of Sciences, Prague, Czech Republic.Departmento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32597009

Citation

Castro Machado, Fabricio, et al. "EIF2α Phosphorylation Is Regulated in Intracellular Amastigotes for the Generation of Infective Trypanosoma Cruzi Trypomastigote Forms." Cellular Microbiology, 2020, pp. e13243.
Castro Machado F, Bittencourt-Cunha P, Malvezzi AM, et al. EIF2α phosphorylation is regulated in intracellular amastigotes for the generation of infective Trypanosoma cruzi trypomastigote forms. Cell Microbiol. 2020.
Castro Machado, F., Bittencourt-Cunha, P., Malvezzi, A. M., Arico, M., Radio, S., Smircich, P., Zoltner, M., Field, M. C., & Schenkman, S. (2020). EIF2α phosphorylation is regulated in intracellular amastigotes for the generation of infective Trypanosoma cruzi trypomastigote forms. Cellular Microbiology, e13243. https://doi.org/10.1111/cmi.13243
Castro Machado F, et al. EIF2α Phosphorylation Is Regulated in Intracellular Amastigotes for the Generation of Infective Trypanosoma Cruzi Trypomastigote Forms. Cell Microbiol. 2020 Jun 29;e13243. PubMed PMID: 32597009.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EIF2α phosphorylation is regulated in intracellular amastigotes for the generation of infective Trypanosoma cruzi trypomastigote forms. AU - Castro Machado,Fabricio, AU - Bittencourt-Cunha,Paula, AU - Malvezzi,Amaranta Muniz, AU - Arico,Mirella, AU - Radio,Santiago, AU - Smircich,Pablo, AU - Zoltner,Martin, AU - Field,Mark C, AU - Schenkman,Sergio, Y1 - 2020/06/29/ PY - 2018/05/08/received PY - 2020/06/15/revised PY - 2020/06/18/accepted PY - 2020/7/1/pubmed PY - 2020/7/1/medline PY - 2020/6/30/entrez KW - Trypanosoma cruzi KW - differentiation KW - eIF2 KW - phosphorylation KW - translation KW - virulence SP - e13243 EP - e13243 JF - Cellular microbiology JO - Cell. Microbiol. N2 - Trypanosomatids regulate gene expression mainly at the post-transcriptional level through processing, exporting and stabilising mRNA and control of translation. In most eukaryotes, protein synthesis is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2) at serine 51. Phosphorylation halts overall translation by decreasing availability of initiator tRNAmet to form translating ribosomes. In trypanosomatids, the N-terminus of eIF2α is extended with threonine 169 the homologous phosphorylated residue. Here, we evaluated whether eIF2α phosphorylation varies during the Trypanosoma cruzi life cycle, the etiological agent of Chagas' disease. Total levels of eIF2α are diminished in infective and non-replicative trypomastigotes compared with proliferative forms from the intestine of the insect vector or amastigotes from mammalian cells, consistent with decreased protein synthesis reported in infective forms. eIF2α phosphorylation increases in proliferative intracellular forms prior to differentiation into trypomastigotes. Parasites overexpressing eIF2αT169A or with an endogenous CRISPR/Cas9-generated eIF2αT169A mutation were created and analysis revealed alterations to the proteome, largely unrelated to the presence of μORF in epimastigotes. eIF2αT169A mutant parasites produced fewer trypomastigotes with lower infectivity than wild type, with increased levels of sialylated mucins and oligomannose glycoproteins, and decreased galactofuranose epitopes and the surface protease GP63 on the cell surface. We conclude that eIF2α expression and phosphorylation levels affect proteins relevant for intracellular progression of T. cruzi. SN - 1462-5822 UR - https://www.unboundmedicine.com/medline/citation/32597009/EIF2α_phosphorylation_is_regulated_in_intracellular_amastigotes_for_generation_of_infective_Trypanosoma_cruzi_trypomastigote_forms L2 - https://doi.org/10.1111/cmi.13243 DB - PRIME DP - Unbound Medicine ER -
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