| First Author | Rada P | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 6 | Pages | 1121-33 |
| PubMed ID | 21245377 | Mgi Jnum | J:170616 |
| Mgi Id | MGI:4946981 | Doi | 10.1128/MCB.01204-10 |
| Citation | Rada P, et al. (2011) SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31(6):1121-33 |
| abstractText | 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/beta-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(DeltaETGE) 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(DeltaETGE 6S/6A) protein, lacking these Ser residues, exhibited a longer half-life than Nrf2(DeltaETGE). Moreover, Nrf2(DeltaETGE 6S/6A) was insensitive to beta-TrCP regulation and exhibited lower levels of ubiquitination than Nrf2(DeltaETGE). GSK-3beta enhanced ubiquitination of Nrf2(DeltaETGE) but not that of Nrf2(DeltaETGE 6S/6A). The Nrf2(DeltaETGE) protein but not Nrf2(DeltaETGE 6S/6A) coimmunoprecipitated with beta-TrCP, and this association was enhanced by GSK-3beta. Our results show for the first time that Nrf2 is targeted by GSK-3 for SCF/beta-TrCP-dependent degradation. We propose a 'dual degradation' model to describe the regulation of Nrf2 under different pathophysiological conditions. |
