Decorin-Evoked Paternally Expressed Gene 3 (PEG3) is an Upstream Regulator of the Transcription Factor EB (TFEB) in Endothelial Cell Autophagy [Cell Biology]

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 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 HUVEC and PAER2 cells. Mechanistically, inhibiting VEGFR2 or 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.

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