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

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

Author information

1
From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
2
Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
3
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
4
Excellence Cluster Cardiopulmonary System (ECCPS), Justus-Liebig-University Giessen, Department of Internal Medicine, Universities of Giessen and Marburg Lung Centre (UGMLC), 35392 Giessen, Germany, and.
5
Department of Thoracic Surgery, University Hospital of Vienna, A-1090 Vienna, Austria.
6
From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany, melchner@em.uni-frankfurt.de.

Abstract

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)

PMID:
25716320
PMCID:
PMC4392273
DOI:
10.1074/jbc.M114.632133
[Indexed for MEDLINE]
Free PMC Article

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