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Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6

Leishmania parasites are digenetic protists that shuffle between sand fly vectors and mammalian hosts, transforming from flagellated extracellular promastigotes that reside within the intestinal tract of female sand flies to the obligatory intracellular and non-motile amastigotes within mammalian ma...

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Autores principales: Tupperwar, Nitin, Shrivastava, Rohit, Baron, Nofar, Korchev, Orli, Dahan, Irit, Shapira, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657474/
https://www.ncbi.nlm.nih.gov/pubmed/34884522
http://dx.doi.org/10.3390/ijms222312720
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author Tupperwar, Nitin
Shrivastava, Rohit
Baron, Nofar
Korchev, Orli
Dahan, Irit
Shapira, Michal
author_facet Tupperwar, Nitin
Shrivastava, Rohit
Baron, Nofar
Korchev, Orli
Dahan, Irit
Shapira, Michal
author_sort Tupperwar, Nitin
collection PubMed
description Leishmania parasites are digenetic protists that shuffle between sand fly vectors and mammalian hosts, transforming from flagellated extracellular promastigotes that reside within the intestinal tract of female sand flies to the obligatory intracellular and non-motile amastigotes within mammalian macrophages. Stage differentiation is regulated mainly by post-transcriptional mechanisms, including translation regulation. Leishmania parasites encode six different cap-binding proteins, LeishIF4E1-6, that show poor conservation with their counterparts from higher eukaryotes and among themselves. In view of the changing host milieu encountered throughout their life cycle, we propose that each LeishIF4E has a unique role, although these functions may be difficult to determine. Here we characterize LeishIF4E-6, a unique eIF4E ortholog that does not readily associate with m(7)GTP cap in either of the tested life forms of the parasite. We discuss the potential effect of substituting two essential tryptophan residues in the cap-binding pocket, expected to be involved in the cap-binding activity, as judged from structural studies in the mammalian eIF4E. LeishIF4E-6 binds to LeishIF4G-5, one of the five eIF4G candidates in Leishmania. However, despite this binding, LeishIF4E-6 does not appear to function as a translation factor. Its episomal overexpression causes a general reduction in the global activity of protein synthesis, which was not observed in the hemizygous deletion mutant generated by CRISPR-Cas9. This genetic profile suggests that LeishIF4E-6 has a repressive role. The interactome of LeishIF4E-6 highlights proteins involved in RNA metabolism such as the P-body marker DHH1, PUF1 and an mRNA-decapping enzyme that is homologous to the TbALPH1.
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spelling pubmed-86574742021-12-10 Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6 Tupperwar, Nitin Shrivastava, Rohit Baron, Nofar Korchev, Orli Dahan, Irit Shapira, Michal Int J Mol Sci Article Leishmania parasites are digenetic protists that shuffle between sand fly vectors and mammalian hosts, transforming from flagellated extracellular promastigotes that reside within the intestinal tract of female sand flies to the obligatory intracellular and non-motile amastigotes within mammalian macrophages. Stage differentiation is regulated mainly by post-transcriptional mechanisms, including translation regulation. Leishmania parasites encode six different cap-binding proteins, LeishIF4E1-6, that show poor conservation with their counterparts from higher eukaryotes and among themselves. In view of the changing host milieu encountered throughout their life cycle, we propose that each LeishIF4E has a unique role, although these functions may be difficult to determine. Here we characterize LeishIF4E-6, a unique eIF4E ortholog that does not readily associate with m(7)GTP cap in either of the tested life forms of the parasite. We discuss the potential effect of substituting two essential tryptophan residues in the cap-binding pocket, expected to be involved in the cap-binding activity, as judged from structural studies in the mammalian eIF4E. LeishIF4E-6 binds to LeishIF4G-5, one of the five eIF4G candidates in Leishmania. However, despite this binding, LeishIF4E-6 does not appear to function as a translation factor. Its episomal overexpression causes a general reduction in the global activity of protein synthesis, which was not observed in the hemizygous deletion mutant generated by CRISPR-Cas9. This genetic profile suggests that LeishIF4E-6 has a repressive role. The interactome of LeishIF4E-6 highlights proteins involved in RNA metabolism such as the P-body marker DHH1, PUF1 and an mRNA-decapping enzyme that is homologous to the TbALPH1. MDPI 2021-11-24 /pmc/articles/PMC8657474/ /pubmed/34884522 http://dx.doi.org/10.3390/ijms222312720 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tupperwar, Nitin
Shrivastava, Rohit
Baron, Nofar
Korchev, Orli
Dahan, Irit
Shapira, Michal
Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title_full Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title_fullStr Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title_full_unstemmed Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title_short Characterization of an Atypical eIF4E Ortholog in Leishmania, LeishIF4E-6
title_sort characterization of an atypical eif4e ortholog in leishmania, leishif4e-6
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657474/
https://www.ncbi.nlm.nih.gov/pubmed/34884522
http://dx.doi.org/10.3390/ijms222312720
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