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The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation

Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related s...

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Autores principales: Wei, Yongjie, An, Zhenyi, Zou, Zhongju, Sumpter, Rhea, Su, Minfei, Zang, Xiao, Sinha, Sangita, Gaestel, Matthias, Levine, Beth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337728/
https://www.ncbi.nlm.nih.gov/pubmed/25693418
http://dx.doi.org/10.7554/eLife.05289
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author Wei, Yongjie
An, Zhenyi
Zou, Zhongju
Sumpter, Rhea
Su, Minfei
Zang, Xiao
Sinha, Sangita
Gaestel, Matthias
Levine, Beth
author_facet Wei, Yongjie
An, Zhenyi
Zou, Zhongju
Sumpter, Rhea
Su, Minfei
Zang, Xiao
Sinha, Sangita
Gaestel, Matthias
Levine, Beth
author_sort Wei, Yongjie
collection PubMed
description Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress-responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1. DOI: http://dx.doi.org/10.7554/eLife.05289.001
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spelling pubmed-43377282015-03-04 The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation Wei, Yongjie An, Zhenyi Zou, Zhongju Sumpter, Rhea Su, Minfei Zang, Xiao Sinha, Sangita Gaestel, Matthias Levine, Beth eLife Biochemistry Autophagy is a fundamental adaptive response to amino acid starvation orchestrated by conserved gene products, the autophagy (ATG) proteins. However, the cellular cues that activate the function of ATG proteins during amino acid starvation are incompletely understood. Here we show that two related stress-responsive kinases, members of the p38 mitogen-activated protein kinase (MAPK) signaling pathway MAPKAPK2 (MK2) and MAPKAPK3 (MK3), positively regulate starvation-induced autophagy by phosphorylating an essential ATG protein, Beclin 1, at serine 90, and that this phosphorylation site is essential for the tumor suppressor function of Beclin 1. Moreover, MK2/MK3-dependent Beclin 1 phosphorylation (and starvation-induced autophagy) is blocked in vitro and in vivo by BCL2, a negative regulator of Beclin 1. Together, these findings reveal MK2/MK3 as crucial stress-responsive kinases that promote autophagy through Beclin 1 S90 phosphorylation, and identify the blockade of MK2/3-dependent Beclin 1 S90 phosphorylation as a mechanism by which BCL2 inhibits the autophagy function of Beclin 1. DOI: http://dx.doi.org/10.7554/eLife.05289.001 eLife Sciences Publications, Ltd 2015-02-18 /pmc/articles/PMC4337728/ /pubmed/25693418 http://dx.doi.org/10.7554/eLife.05289 Text en © 2015, Wei et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Wei, Yongjie
An, Zhenyi
Zou, Zhongju
Sumpter, Rhea
Su, Minfei
Zang, Xiao
Sinha, Sangita
Gaestel, Matthias
Levine, Beth
The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title_full The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title_fullStr The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title_full_unstemmed The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title_short The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
title_sort stress-responsive kinases mapkapk2/mapkapk3 activate starvation-induced autophagy through beclin 1 phosphorylation
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337728/
https://www.ncbi.nlm.nih.gov/pubmed/25693418
http://dx.doi.org/10.7554/eLife.05289
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