Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.

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.

• Authors: Xu Qian, Xinjian Li, Qingsong Cai, Chuanbao Zhang, Qiujing Yu, Yuhui Jiang, Jong-Ho Lee, David Hawke, Yugang Wang, Yan Xia, Yanhua Zheng, Bing-Hua Jiang, David X Liu, Tao Jiang, Zhimin Lu
• Journal: Molecular cell (Mol Cell) Vol. 65 Issue 5 Pg. 917-931.e6 (Mar 02 2017) ISSN: 1097-4164 [Electronic] United States
• PMID: 28238651 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• BECN1 protein, human
• Beclin-1
• Glutamine
• N-Terminal Acetyltransferase A
• NAA10 protein, human
• N-Terminal Acetyltransferase E
• MTOR protein, human
• Class III Phosphatidylinositol 3-Kinases
• TOR Serine-Threonine Kinases
• PGK1 protein, human
• Phosphoglycerate Kinase

Topics

• Acetylation
• Animals
• Autophagosomes (enzymology, pathology)
• Autophagy
• Beclin-1 (genetics, metabolism)
• Brain Neoplasms (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Class III Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Female
• Glioblastoma (enzymology, genetics, pathology)
• Glutamine (deficiency)
• HEK293 Cells
• Humans
• Mice, Nude
• N-Terminal Acetyltransferase A (genetics, metabolism)
• N-Terminal Acetyltransferase E (genetics, metabolism)
• Phosphoglycerate Kinase (genetics, metabolism)
• Phosphorylation
• Protein Binding
• RNA Interference
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Time Factors
• Transfection
• Tumor Burden
• Tumor Hypoxia