ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy

Mol Cell. 2016 May 5;62(3):359-370. doi: 10.1016/j.molcel.2016.04.009.

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.

MeSH terms

  • Amino Acids / deficiency
  • Amino Acids / metabolism
  • Animals
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog / deficiency
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Biomarkers, Tumor / metabolism
  • Cell Death
  • DNA-Binding Proteins / metabolism
  • Female
  • Fructose-Bisphosphatase / metabolism
  • Genotype
  • Glucose / metabolism*
  • Glycolysis*
  • HCT116 Cells
  • Hexokinase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MCF-7 Cells
  • Male
  • Mice, Knockout
  • Pentose Phosphate Pathway*
  • Phenotype
  • Phosphofructokinase-1 / metabolism
  • Phosphopyruvate Hydratase / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Stress, Physiological*
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins / metabolism

Substances

  • Amino Acids
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • HK1 protein, human
  • HK1 protein, mouse
  • Hexokinase
  • Phosphofructokinase-1
  • Ulk2 protein, mouse
  • Autophagy-Related Protein-1 Homolog
  • Protein Serine-Threonine Kinases
  • ULK1 protein, human
  • Ulk1 protein, mouse
  • Ulk2 protein, human
  • Fructose-Bisphosphatase
  • ENO1 protein, human
  • Eno1 protein, mouse
  • Phosphopyruvate Hydratase
  • Glucose