Sestrin 2 protein regulates platelet-derived growth factor receptor β (Pdgfrβ) expression by modulating proteasomal and Nrf2 transcription factor functions

J Biol Chem. 2015 Apr 10;290(15):9738-52. doi: 10.1074/jbc.M114.632133. Epub 2015 Feb 25.


We recently identified the antioxidant protein Sestrin 2 (Sesn2) as a suppressor of platelet-derived growth factor receptor β (Pdgfrβ) signaling and Pdgfrβ signaling as an inducer of lung regeneration and injury repair. Here, we identified Sesn2 and the antioxidant gene inducer nuclear factor erythroid 2-related factor 2 (Nrf2) as positive regulators of proteasomal function. Inactivation of Sesn2 or Nrf2 induced reactive oxygen species-mediated proteasomal inhibition and Pdgfrβ accumulation. Using bacterial artificial chromosome (BAC) transgenic HeLa and mouse embryonic stem cells stably expressing enhanced green fluorescent protein-tagged Sesn2 at nearly endogenous levels, we also showed that Sesn2 physically interacts with 2-Cys peroxiredoxins and Nrf2 albeit under different reductive conditions. Overall, we characterized a novel, redox-sensitive Sesn2/Pdgfrβ suppressor pathway that negatively interferes with lung regeneration and is up-regulated in the emphysematous lungs of patients with chronic obstructive pulmonary disease (COPD).

Keywords: Chronic Obstructive Pulmonary Disease (COPD); Nuclear Factor 2 (Erythroid-derived 2-like Factor) (NFE2L2) (Nrf2); Peroxiredoxin; Proteasome; Reactive Oxygen Species (ROS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Cell Line
  • Cells, Cultured
  • Female
  • Fibroblasts / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice, Knockout
  • Microscopy, Confocal
  • Middle Aged
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Signal Transduction / genetics
  • Young Adult


  • NF-E2-Related Factor 2
  • Nuclear Proteins
  • Reactive Oxygen Species
  • SESN2 protein, human
  • Receptor, Platelet-Derived Growth Factor beta
  • Proteasome Endopeptidase Complex