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

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

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Authors

  • Patricia Rada
  • Ana I. Rojo
  • Nathalie Evrard-Todeschi
  • Nadia G. Innamorato
  • Axelle Cotte
  • Tomasz Jaworski
  • Julio C. Tobón-Velasco
  • Herman Devijver
  • María Flor García-Mayoral
  • Fred Van Leuven
  • John D. Hayes
  • Gildas Bertho
  • Antonio Cuadrado

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Info

Original languageEnglish
Pages3486-99
Number of pages14
JournalMolecular and Cellular Biology
Journal publication date2012
Volume32
Issue17
DOIs
StatePublished

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 ß-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 3ß (GSK-3ß) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of ß-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of ß-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-3ß 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/ß-TrCP axis and its functional relevance in the regulation of Nrf2 by the signaling pathways that impinge on GSK-3.

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