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Mol Cell. 2017 Mar 2;65(5):917-931.e6. doi: 10.1016/j.molcel.2017.01.027. Epub 2017 Feb 23.

Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.

Author information

1
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
3
The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
4
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The Institute of Cell Metabolism and Diseases, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
5
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
State Key Lab of Reproductive Medicine, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Department of Pathology, Nanjing Medical University, Nanjing 210029, China.
7
Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99202, USA.
8
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: zhiminlu@mdanderson.org.

Abstract

Autophagy is crucial for maintaining cell homeostasis. However, the precise mechanism underlying autophagy initiation remains to be defined. Here, we demonstrate that glutamine deprivation and hypoxia result in inhibition of mTOR-mediated acetyl-transferase ARD1 S228 phosphorylation, leading to ARD1-dependent phosphoglycerate kinase 1 (PGK1) K388 acetylation and subsequent PGK1-mediated Beclin1 S30 phosphorylation. This phosphorylation enhances ATG14L-associated class III phosphatidylinositol 3-kinase VPS34 activity by increasing the binding of phosphatidylinositol to VPS34. ARD1-dependent PGK1 acetylation and PGK1-mediated Beclin1 S30 phosphorylation are required for glutamine deprivation- and hypoxia-induced autophagy and brain tumorigenesis. Furthermore, PGK1 K388 acetylation levels correlate with Beclin1 S30 phosphorylation levels and poor prognosis in glioblastoma patients. Our study unearths an important mechanism underlying cellular-stress-induced autophagy initiation in which the protein kinase activity of the metabolic enzyme PGK1 plays an instrumental role and reveals the significance of the mutual regulation of autophagy and cell metabolism in maintaining cell homeostasis.

KEYWORDS:

ARD1; Beclin1; PGK1; VPS34; autophagy; mTOR; tumor

PMID:
28238651
PMCID:
PMC5389741
DOI:
10.1016/j.molcel.2017.01.027
[Indexed for MEDLINE]
Free PMC Article

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