Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein

Nathan D. Camp, Richard G. James, David W. Dawson, Feng Yan, James M. Davison, Scott A. Houck, Xiaobo Tang, Ning Zheng, Michael B. Major, Randall T. Moon

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)6539-6550
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number9
DOIs
StatePublished - Feb 24 2012
Externally publishedYes

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    Camp, N. D., James, R. G., Dawson, D. W., Yan, F., Davison, J. M., Houck, S. A., Tang, X., Zheng, N., Major, M. B., & Moon, R. T. (2012). Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. Journal of Biological Chemistry, 287(9), 6539-6550. https://doi.org/10.1074/jbc.M111.316471