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Title

Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis

AuthorsRada, Patricia; Rojo, Ana I. ; Innamorato, Nadia G.; Tobón-Velasco, Julio C.; García-Mayoral, M.F. ; Hayes, John D.; Cuadrado, Antonio
KeywordsNF-E2-related factor 2
Nrf2
Redox homeostasis
GSK-3β
Issue Date30-Sep-2012
PublisherAmerican Society for Microbiology
CitationMolecular and Cellular Biology 32(17): 3486-3499 (2012)
AbstractThe 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-3β exhibited 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.
Publisher version (URL)http://dx.doi.org/10.1128/​MCB.00180-12
URIhttp://hdl.handle.net/10261/57984
DOI10.1128/​MCB.00180-12
ISSN0270-7306
E-ISSN1098-5549
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