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

Yongjie Wei, Zhenyi An, Zhongju Zou, Rhea Sumpter, Minfei Su, Xiao Zang, Sangita Sinha, Matthias Gaestel, Beth Levine

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere05289
JournaleLife
Volume2015
Issue number4
DOIs
StatePublished - Feb 18 2015

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Phosphorylation
Autophagy
Starvation
Phosphotransferases
Amino Acids
Proteins
p38 Mitogen-Activated Protein Kinases
Serine
Tumors
Genes
Beclin-1
MAP-kinase-activated kinase 2
MAP-kinase-activated kinase 3
Cues

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

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.

In: eLife, Vol. 2015, No. 4, e05289, 18.02.2015.

Research output: Contribution to journalArticle

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. In: eLife. 2015 ; Vol. 2015, No. 4.
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AU - Zou, Zhongju

AU - Sumpter, Rhea

AU - Su, Minfei

AU - Zang, Xiao

AU - Sinha, Sangita

AU - Gaestel, Matthias

AU - Levine, Beth

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