Wilms Tumor Gene on X Chromosome (WTX) Inhibits Degradation of NRF2 Protein through Competitive Binding to KEAP1 Protein

WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the β-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor β-catenin,...

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Bibliographic Details
Published in:	The Journal of biological chemistry 2012-02, Vol.287 (9), p.6539-6550
Main Authors:	Camp, Nathan D., James, Richard G., Dawson, David W., Yan, Feng, Davison, James M., Houck, Scott A., Tang, Xiaobo, Zheng, Ning, Major, Michael B., Moon, Randall T.
Format:	Article
Language:	eng
Subjects:	adaptor proteins Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Antioxidants Antioxidants - metabolism beta-Transducin Repeat-Containing Proteins - metabolism Binding, Competitive - physiology BTRC catenin Chromosomes, Human, X - genetics Cytotoxicity HEK293 Cells Humans Intracellular Signaling Peptides and Proteins - metabolism KEAP1 Kelch-Like ECH-Associated Protein 1 Molecular modelling NF-E2-Related Factor 2 - metabolism Nrf2 NRF2 protein Phosphorylation - physiology RNA, Small Interfering - genetics Serine - metabolism Signal Transduction Transcription factors Transcriptional Activation - physiology Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Ubiquitin Ubiquitin-protein ligase Ubiquitination Ubiquitination - physiology Wilms Tumor - genetics Wilms Tumor - metabolism Wnt protein WTX X chromosome
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Summary:	WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the β-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor β-catenin, a key control point in the WNT/β-catenin signaling pathway. Here, we report that WTX interacts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of the transcription factor NRF2, a key control point in the antioxidant response. Surprisingly, we find that unlike its ability to promote the ubiquitination of β-catenin, WTX inhibits the ubiquitination of NRF2. WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. These results expand our understanding of the molecular mechanisms of WTX and reveal a novel regulatory mechanism governing the antioxidant response. KEAP1 is a ubiquitin ligase adaptor that promotes the ubiquitination and degradation of NRF2, a transcription factor that drives the antioxidant response. Wilms tumor gene on the X chromosome (WTX) stabilizes NRF2 by competing with NRF2 for binding to KEAP1. WTX regulates the antioxidant response. This study reveals a novel regulatory mechanism governing the antioxidant response.
ISSN:	0021-9258 1083-351X