The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation
Yongjie Wei,
Zhenyi An,
Zhongju Zou,
Rhea Sumpter Jr,
Minfei Su,
Xiao Zang,
Sangita Sinha,
Matthias Gaestel,
Beth Levine
Affiliations
Yongjie Wei
Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, United States
Zhenyi An
Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
Zhongju Zou
Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, United States
Rhea Sumpter Jr
Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
Minfei Su
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, United States
Xiao Zang
Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, United States
Sangita Sinha
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, United States
Matthias Gaestel
Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany
Beth Levine
Center for Autophagy Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, United States; Department of Microbiology, UT Southwestern Medical Center, Dallas, United States
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.
