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4E-T-bound mRNAs are stored in a silenced and deadenylated form

Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T...

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Autores principales: Räsch, Felix, Weber, Ramona, Izaurralde, Elisa, Igreja, Cátia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263148/
https://www.ncbi.nlm.nih.gov/pubmed/32354837
http://dx.doi.org/10.1101/gad.336073.119
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author Räsch, Felix
Weber, Ramona
Izaurralde, Elisa
Igreja, Cátia
author_facet Räsch, Felix
Weber, Ramona
Izaurralde, Elisa
Igreja, Cátia
author_sort Räsch, Felix
collection PubMed
description Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T represses translation and promotes deadenylation via the recruitment of the CCR4–NOT deadenylase complex. The interaction with CCR4–NOT is mediated by previously uncharacterized sites in the middle region of 4E-T. Importantly, mRNA decapping and decay are inhibited by 4E-T and the deadenylated target is stored in a repressed form. Inhibition of mRNA decapping requires the interaction of 4E-T with the cap-binding proteins eIF4E/4EHP. We further show that regulation of decapping by 4E-T participates in mRNA repression by the miRNA effector protein TNRC6B and that 4E-T overexpression interferes with tristetraprolin (TTP)- and NOT1-mediated mRNA decay. Thus, we postulate that 4E-T modulates 5′-to-3′ decay by swapping the fate of a deadenylated mRNA from complete degradation to storage. Our results provide insight into the mechanism of mRNA storage that controls localized translation and mRNA stability in P-bodies.
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spelling pubmed-72631482020-06-10 4E-T-bound mRNAs are stored in a silenced and deadenylated form Räsch, Felix Weber, Ramona Izaurralde, Elisa Igreja, Cátia Genes Dev Research Paper Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T represses translation and promotes deadenylation via the recruitment of the CCR4–NOT deadenylase complex. The interaction with CCR4–NOT is mediated by previously uncharacterized sites in the middle region of 4E-T. Importantly, mRNA decapping and decay are inhibited by 4E-T and the deadenylated target is stored in a repressed form. Inhibition of mRNA decapping requires the interaction of 4E-T with the cap-binding proteins eIF4E/4EHP. We further show that regulation of decapping by 4E-T participates in mRNA repression by the miRNA effector protein TNRC6B and that 4E-T overexpression interferes with tristetraprolin (TTP)- and NOT1-mediated mRNA decay. Thus, we postulate that 4E-T modulates 5′-to-3′ decay by swapping the fate of a deadenylated mRNA from complete degradation to storage. Our results provide insight into the mechanism of mRNA storage that controls localized translation and mRNA stability in P-bodies. Cold Spring Harbor Laboratory Press 2020-06-01 /pmc/articles/PMC7263148/ /pubmed/32354837 http://dx.doi.org/10.1101/gad.336073.119 Text en © 2020 Räsch et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Räsch, Felix
Weber, Ramona
Izaurralde, Elisa
Igreja, Cátia
4E-T-bound mRNAs are stored in a silenced and deadenylated form
title 4E-T-bound mRNAs are stored in a silenced and deadenylated form
title_full 4E-T-bound mRNAs are stored in a silenced and deadenylated form
title_fullStr 4E-T-bound mRNAs are stored in a silenced and deadenylated form
title_full_unstemmed 4E-T-bound mRNAs are stored in a silenced and deadenylated form
title_short 4E-T-bound mRNAs are stored in a silenced and deadenylated form
title_sort 4e-t-bound mrnas are stored in a silenced and deadenylated form
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263148/
https://www.ncbi.nlm.nih.gov/pubmed/32354837
http://dx.doi.org/10.1101/gad.336073.119
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