title: 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.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Li
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Chuanbao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hawke
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA 99202, USA.
authors.forename: David X
authors.initials: DX
authors.lastname: Liu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000107:Acetylation; D000818:Animals; D000071182:Autophagosomes / Q000201:enzymology* / Q000473:pathology; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005973:Glutamine / Q000172:deficiency; D057809:HEK293 Cells; D006801:Humans; D008819:Mice, Nude; D063209:N-Terminal Acetyltransferase A / Q000235:genetics / Q000378:metabolism; D063213:N-Terminal Acetyltransferase E / Q000235:genetics / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000072258:Tumor Hypoxia
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; D005973:Glutamine; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E; C546842:MTOR protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C577282:PGK1 protein, human; D010735:Phosphoglycerate Kinase
keywords: ARD1; Beclin1; PGK1; VPS34; autophagy; mTOR; tumor