title: Sestrin 2 protein regulates platelet-derived growth factor receptor β (Pdgfrβ) expression by modulating proteasomal and Nrf2 transcription factor functions.
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).
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Tomasovic
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Kurrle
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Duran
authors.initials: D
authors.lastname: Sürün
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.affiliation: Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Koraljka
authors.initials: K
authors.lastname: Husnjak
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schnütgen
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Scheibe
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Seimetz
authors.affiliation: Department of Thoracic Surgery, University Hospital of Vienna, A-1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Jaksch
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
authors.forename: Anthony
authors.initials: A
authors.lastname: Hyman
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: From the Department of Molecular Hematology, Goethe University Medical School, 60590 Frankfurt am Main, Germany, melchner@em.uni-frankfurt.de.
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult; D000084622:Sestrins
chemical_list: D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D017382:Reactive Oxygen Species; D020797:Receptor, Platelet-Derived Growth Factor beta; C465398:SESN2 protein, human; D000084622:Sestrins
keywords: Chronic Obstructive Pulmonary Disease (COPD); Nuclear Factor 2 (Erythroid-derived 2-like Factor) (NFE2L2) (Nrf2); Peroxiredoxin; Proteasome; Reactive Oxygen Species (ROS)