The unique Leishmania EIF4E4 N-terminus is a target for multiple phosphorylation events and participates in critical interactions required for translation initiation

RNA Biology
Osvaldo P de Melo NetoBarbara Papadopoulou

Abstract

The eukaryotic initiation factor 4E (eIF4E) recognizes the mRNA cap structure and, together with eIF4G and eIF4A, form the eIF4F complex that regulates translation initiation in eukaryotes. In trypanosomatids, 2 eIF4E homologues (EIF4E3 and EIF4E4) have been shown to be part of eIF4F-like complexes with presumed roles in translation initiation. Both proteins possess unique N-terminal extensions, which can be targeted for phosphorylation. Here, we provide novel insights on the Leishmania infantum EIF4E4 function and regulation. We show that EIF4E4 is constitutively expressed throughout the parasite development but is preferentially phosphorylated in exponentially grown promastigote and amastigote life stages, hence correlating with high levels of translation. Phosphorylation targets multiple serine-proline or threonine-proline residues within the N-terminal extension of EIF4E4 but does not require binding to the EIF4E4's partner, EIF4G3, or to the cap structure. We also report that EIF4E4 interacts with PABP1 through 3 conserved boxes at the EIF4E4 N-terminus and that this interaction is a prerequisite for efficient EIF4E4 phosphorylation. EIF4E4 is essential for Leishmania growth and an EIF4E4 null mutant was only obtained in t...Continue Reading

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Citations

Jul 25, 2018·PLoS Neglected Tropical Diseases·Martin ZoltnerSusanne Kramer
Nov 27, 2018·Nucleic Acids Research·Fabio Henrique Dos Santos RodriguesJohn E G McCarthy
Mar 15, 2019·PLoS Neglected Tropical Diseases·Rohit ShrivastavaMichal Shapira
Apr 5, 2020·International Journal of Molecular Sciences·Daniela Ross-Kaschitza, Michael Altmann
May 5, 2021·RNA Biology·Gustavo Barbosa de LimaOsvaldo Pompílio de-Melo-Neto

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Methods Mentioned

BETA
transfection
pull-down
2-hybrid
Immunoprecipitation
immunoprecipitations
gene knockout
FCS
PCR
in vitro transcription

Software Mentioned

BioEdit Sequence Alignment Editor
ClustalW Multiple alignment
ClustalW2
TriTrypDB
Clustal

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