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

J Biol Chem. 2012 Feb 24;287(9):6539-50. doi: 10.1074/jbc.M111.316471. Epub 2012 Jan 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antioxidants / metabolism*
  • Binding, Competitive / physiology
  • Chromosomes, Human, X / genetics
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphorylation / physiology
  • RNA, Small Interfering / genetics
  • Serine / metabolism
  • Transcriptional Activation / physiology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination / physiology
  • Wilms Tumor / genetics
  • Wilms Tumor / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • AMER1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Antioxidants
  • BTRC protein, human
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • beta-Transducin Repeat-Containing Proteins
  • Serine