title: ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy.
abstract: Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Terytty Yang
authors.initials: TY
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Chen-Song
authors.initials: CS
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Cixiong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Lintao
authors.initials: L
authors.lastname: Song
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Fujian 361102, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Fujian 361102, China.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xiadi
authors.initials: X
authors.lastname: He
authors.affiliation: Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Shaoxuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Canhe
authors.initials: C
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Changchuan
authors.initials: C
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: James Y
authors.initials: JY
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Shu-Yong
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Kwei-san, Tao-yuan 333, Taiwan; Department of Laboratory Medicine, Chang Gung Memorial Hospital, Tau-yuan 333, Taiwan.
authors.forename: Daniel Tsun-Yee
authors.initials: DT
authors.lastname: Chiu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian 361102, China. Electronic address: linsc@xmu.edu.cn.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
mesh_terms: D000596:Amino Acids / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006597:Fructose-Bisphosphatase / Q000378:metabolism; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D045325:HCT116 Cells; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D018345:Mice, Knockout; D010427:Pentose Phosphate Pathway; D010641:Phenotype; D010732:Phosphofructokinase-1 / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000596:Amino Acids; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C472074:HK1 protein, human; C515658:HK1 protein, mouse; D006593:Hexokinase; D010732:Phosphofructokinase-1; C401061:Ulk2 protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; C541703:Ulk2 protein, human; D006597:Fructose-Bisphosphatase; C095157:ENO1 protein, human; C457379:Eno1 protein, mouse; D010751:Phosphopyruvate Hydratase; D005947:Glucose