alexa SCF {beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD,

Abstract Share this page

Abstract Regulation of transcription factor Nrf2 (NF-E2-related factor 2) involves redox-sensitive proteasomal degradation via the E3 ubiquitin ligase Keap1/Cul3. However, Nrf2 is controlled by other mechanisms that have not yet been elucidated. We now show that glycogen synthase kinase 3 (GSK-3) phosphorylates a group of Ser residues in the Neh6 domain of mouse Nrf2 that overlap with an SCF/β-TrCP destruction motif (DSGIS, residues 334 to 338) and promotes its degradation in a Keap1-independent manner. Nrf2 was stabilized by GSK-3 inhibitors in Keap1-null mouse embryo fibroblasts. Similarly, an Nrf2(ΔETGE) mutant, which cannot be degraded via Keap1, accumulated when GSK-3 activity was blocked. Phosphorylation of a Ser cluster in the Neh6 domain of Nrf2 stimulated its degradation because a mutant Nrf2(ΔETGE 6S/6A) protein, lacking these Ser residues, exhibited a longer half-life than Nrf2(ΔETGE). Moreover, Nrf2(ΔETGE 6S/6A) was insensitive to β-TrCP regulation and exhibited lower levels of ubiquitination than Nrf2(ΔETGE). GSK-3β enhanced ubiquitination of Nrf2(ΔETGE) but not that of Nrf2(ΔETGE 6S/6A). The Nrf2(ΔETGE) protein but not Nrf2(ΔETGE 6S/6A) coimmunoprecipitated with β-TrCP, and this association was enhanced by GSK-3β. Our results show for the first time that Nrf2 is targeted by GSK-3 for SCF/β-TrCP-dependent degradation. We propose a "dual degradation" model to describe the regulation of Nrf2 under different pathophysiological conditions.
This article was published in Mol Cell Biol and referenced in Journal of Diabetes & Metabolism

Relevant Expert PPTs

Relevant Speaker PPTs

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords