Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis
Entity
UAM. Departamento de BioquímicaPublisher
American Society for MicrobiologyDate
2012-09-01Citation
10.1128/MCB.00180-12
Molecular and Cellular Biology 32.17 (2012): 3486-3499
ISSN
0270-7306 (print); 1098-5549 (online)DOI
10.1128/MCB.00180-12Funded by
This work was supported by MICINN grant SAF2010-18722 from the Spanish Ministry of Science and Innovation. Patricia Rada is contracted under the Formación de Profesorado Universitario program of the Spanish Ministry of Science and Innovation. We acknowledge funding and infrastructural support from EEC 7th Framework Program, KU Leuven Research Fund, and KU Leuven Research & DevelopmentSubjects
Amino Acid Sequence; Glycogen Synthase Kinase 3; Mutagenesis; transcription factor Nrf2; MedicinaRights
© 2012, American Society for MicrobiologyAbstract
The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of a genetic program, termed the phase 2 response, that controls redox homeostasis and participates in multiple aspects of physiology and pathology. Nrf2 protein stability is regulated by two E3 ubiquitin ligase adaptors, Keap1 and β-TrCP, the latter of which was only recently reported. Here, two-dimensional (2D) gel electrophoresis and site-directed mutagenesis allowed us to identify two serines of Nrf2 that are phosphorylated by glycogen synthase kinase 3β (GSK-3β) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of β-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of β-TrCP that participate in Nrf2 docking. Intraperitoneal injection of the GSK-3 inhibitor SB216763 led to increased Nrf2 and heme oxygenase-1 levels in liver and hippocampus. Moreover, mice with hippocampal absence of GSK-3βexhibited increased levels of Nrf2 and phase 2 gene products, reduced glutathione, and decreased levels of carbonylated proteins and malondialdehyde. This study establishes the structural parameters of the interaction of Nrf2 with the GSK-3/β-TrCP axis and its functional relevance in the regulation of Nrf2 by the signaling pathways that impinge on GSK-3
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Google Scholar:Rada, Patricia
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Rojo Sanchís, Ana Isabel
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Évrard-Todeschi, Nathalie
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Innamorato, Nadia G.
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Cotte, Axelle
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Jaworski, Tomasz
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Tobón-Velasco, Julio César
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Devijver, Herman
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García-Mayoral, María Flor
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Van Leuven, Fred Van
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Hayes, John D.
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Bertho, Gildas
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Cuadrado Pastor, Antonio
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