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

Authors:Rada, Patricia
Rojo, Ana I.
Innamorato, Nadia G.
Tobón-Velasco, Julio C.
García-Mayoral, M. F.
Hayes, John D.
Cuadrado, Antonio
Keywords:NF-E2-related factor 2, Nrf2, Redox homeostasis, GSK-3β
Issue Date:30-Sep-2012
Publisher:American Society for Microbiology
Citation:Molecular and Cellular Biology 32(17): 3486-3499 (2012)
Abstract: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-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
URI:http://hdl.handle.net/10261/57984
ISSN:0270-7306
E-ISSNmetadata.dc.identifier.doi = DOI:1098-5549
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