Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2.

Sekhar KR, Yan XX, Freeman ML
Oncogene. 2002 21 (44): 6829-34

PMID: 12360409 · DOI:10.1038/sj.onc.1205905

INrf2 tethering of the transcription factor Nrf2 in the cytosol prevents Nrf2 activation of antioxidant response element (ARE) mediated gene expression. This investigation was undertaken to determine if tethering affected Nrf2 degradation. Data is presented showing that Nrf2 is degraded by the ubiquitin-proteasome pathway. Nrf2 co-immunoprecipitated with a HA tagged ubiquitin polymer and accumulated in cells expressing inactive ubiquitin activating enzyme El. Inhibition of proteasome activity resulted in accumulation of Nrf2. The rate of Nrf2 degradation, measured under conditions where the majority of Nrf2 was not tethered, exhibited a T(1/2) of approximately 3 h. Over-expression of human INrf2, KIAA0132, blocked Nrf2 conjugation to the ubiquitin polymer and blocked Nrf2 degradation. These results suggest that association of Nrf2 with INrf2 inhibits ubiquitin-proteasome degradation of Nrf2. Maintaining the majority of Nrf2 in a tethered form, resistant to ubiquitin-proteasome dependent degradation, allows a pool of Nrf2 to be available for rapid Nrf2/ARE-dependent gene transcription following stress mediated release from INrf2. Further, the observation that free Nrf2 is degraded by the ubiquitin proteasome pathway provides a potential mechanism by which ARE-dependent gene transcription is attenuated after induction.

MeSH Terms (16)

Animals Antioxidants Cysteine Endopeptidases DNA-Binding Proteins Half-Life Humans Intracellular Signaling Peptides and Proteins Kelch-Like ECH-Associated Protein 1 Mice Multienzyme Complexes NF-E2-Related Factor 2 Proteasome Endopeptidase Complex Proteins Response Elements Trans-Activators Ubiquitin

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