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The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition

Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5′ untranslated regions of mRNAs. Most prior studies of Ded1 cellular function we...

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Autores principales: Aryanpur, Peyman P., Renner, David M., Rodela, Emily, Mittelmeier, Telsa M., Byrd, Aaron, Bolger, Timothy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743465/
https://www.ncbi.nlm.nih.gov/pubmed/31141444
http://dx.doi.org/10.1091/mbc.E18-11-0702
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author Aryanpur, Peyman P.
Renner, David M.
Rodela, Emily
Mittelmeier, Telsa M.
Byrd, Aaron
Bolger, Timothy A.
author_facet Aryanpur, Peyman P.
Renner, David M.
Rodela, Emily
Mittelmeier, Telsa M.
Byrd, Aaron
Bolger, Timothy A.
author_sort Aryanpur, Peyman P.
collection PubMed
description Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5′ untranslated regions of mRNAs. Most prior studies of Ded1 cellular function were conducted in steady-state conditions during nutrient-rich growth. In this work, however, we examine its role in the translational response during target of rapamycin (TOR)C1 inhibition and identify a novel function of Ded1 as a translation repressor. We show that C-terminal mutants of DED1 are defective in down-regulating translation following TORC1 inhibition using rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping of the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein Ded1 stalls translation and specifically removes eIF4G1 from translation preinitiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the codegradation of both proteins. Shared features among DED1 orthologues suggest that this role is conserved and may be implicated in pathologies such as oncogenesis.
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spelling pubmed-67434652019-10-16 The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition Aryanpur, Peyman P. Renner, David M. Rodela, Emily Mittelmeier, Telsa M. Byrd, Aaron Bolger, Timothy A. Mol Biol Cell Articles Ded1 is a DEAD-box RNA helicase with essential roles in translation initiation. It binds to the eukaryotic initiation factor 4F (eIF4F) complex and promotes 48S preinitiation complex assembly and start-site scanning of 5′ untranslated regions of mRNAs. Most prior studies of Ded1 cellular function were conducted in steady-state conditions during nutrient-rich growth. In this work, however, we examine its role in the translational response during target of rapamycin (TOR)C1 inhibition and identify a novel function of Ded1 as a translation repressor. We show that C-terminal mutants of DED1 are defective in down-regulating translation following TORC1 inhibition using rapamycin. Furthermore, following TORC1 inhibition, eIF4G1 normally dissociates from translation complexes and is degraded, and this process is attenuated in mutant cells. Mapping of the functional requirements for Ded1 in this translational response indicates that Ded1 enzymatic activity and interaction with eIF4G1 are required, while homo-oligomerization may be dispensable. Our results are consistent with a model wherein Ded1 stalls translation and specifically removes eIF4G1 from translation preinitiation complexes, thus removing eIF4G1 from the translating mRNA pool and leading to the codegradation of both proteins. Shared features among DED1 orthologues suggest that this role is conserved and may be implicated in pathologies such as oncogenesis. The American Society for Cell Biology 2019-08-01 /pmc/articles/PMC6743465/ /pubmed/31141444 http://dx.doi.org/10.1091/mbc.E18-11-0702 Text en © 2019 Aryanpur et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Articles
Aryanpur, Peyman P.
Renner, David M.
Rodela, Emily
Mittelmeier, Telsa M.
Byrd, Aaron
Bolger, Timothy A.
The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title_full The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title_fullStr The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title_full_unstemmed The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title_short The DEAD-box RNA helicase Ded1 has a role in the translational response to TORC1 inhibition
title_sort dead-box rna helicase ded1 has a role in the translational response to torc1 inhibition
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743465/
https://www.ncbi.nlm.nih.gov/pubmed/31141444
http://dx.doi.org/10.1091/mbc.E18-11-0702
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