Abstract
Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein kinase (AMPK), a major decorin-activated energy sensor kinase, prevented decorin-evoked TFEB induction and nuclear localization. In conclusion, our findings indicate a non-canonical (nutrient- and energy-independent) mechanism underlying the pro-autophagic bioactivity of decorin via PEG3 and TFEB.
Keywords:
VEGF; autophagy; decorin; endothelial cell; proteoglycan.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / metabolism
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Active Transport, Cell Nucleus / drug effects
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Animals
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Aorta / cytology
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Aorta / drug effects
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Aorta / metabolism
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Autophagy* / drug effects
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / agonists*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Cells, Cultured
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Decorin / genetics
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Decorin / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Gene Expression Regulation / drug effects
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Kruppel-Like Transcription Factors / chemistry
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Receptors, Growth Factor / agonists*
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Receptors, Growth Factor / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Signal Transduction* / drug effects
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Sus scrofa
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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DCN protein, human
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Decorin
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Kruppel-Like Transcription Factors
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PEG3 protein, human
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Peptide Fragments
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Protein Kinase Inhibitors
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Receptors, Growth Factor
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Recombinant Fusion Proteins
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Recombinant Proteins
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TFEB protein, human
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decorin receptor
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
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AMP-Activated Protein Kinases