PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites.

Autor:	Ferreira TR; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Dowle AA; Metabolomics and Proteomics Lab, Bioscience Technology Facility, Department of Biology, University of York, UK., Parry E; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Alves-Ferreira EVC; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Hogg K; Imaging and Cytometry Lab, Bioscience Technology Facility, Department of Biology, University of York, UK., Kolokousi F; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Larson TR; Metabolomics and Proteomics Lab, Bioscience Technology Facility, Department of Biology, University of York, UK., Plevin MJ; York Biomedical Research Institute, Department of Biology, University of York, York, UK., Cruz AK; Cell and Molecular Biology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil., Walrad PB; York Biomedical Research Institute, Department of Biology, University of York, York, UK.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2020 Jun 04; Vol. 48 (10), pp. 5511-5526.
DOI:	10.1093/nar/gkaa211
Abstrakt:	RNA binding proteins (RBPs) are the primary gene regulators in kinetoplastids as transcriptional control is nearly absent, making Leishmania an exceptional model for investigating methylation of non-histone substrates. Arginine methylation is an evolutionarily conserved protein modification catalyzed by Protein aRginine Methyl Transferases (PRMTs). The chromatin modifier PRMT7 is the only Type III PRMT found in higher eukaryotes and a restricted number of unicellular eukaryotes. In Leishmania major, PRMT7 is a cytoplasmic protein implicit in pathogenesis with unknown substrates. Using comparative methyl-SILAC proteomics for the first time in protozoa, we identified 40 putative targets, including 17 RBPs hypomethylated upon PRMT7 knockout. PRMT7 can modify Alba3 and RBP16 trans-regulators (mammalian RPP25 and YBX2 homologs, respectively) as direct substrates in vitro. The absence of PRMT7 levels in vivo selectively reduces Alba3 mRNA-binding capacity to specific target transcripts and can impact the relative stability of RBP16 in the cytoplasm. RNA immunoprecipitation analyses demonstrate PRMT7-dependent methylation promotes Alba3 association with select target transcripts and thus indirectly stabilizes mRNA of a known virulence factor, δ-amastin surface antigen. These results highlight a novel role for PRMT7-mediated arginine methylation of RBP substrates, suggesting a regulatory pathway controlling gene expression and virulence in Leishmania. This work introduces Leishmania PRMTs as epigenetic regulators of mRNA metabolism with mechanistic insight into the functional manipulation of RBPs by methylation. (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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