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, 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.
Howard Hughes Medical Institute, Department of Pharmacology, Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Nathan D
ND
Camp
Richard G
RG
James
David W
DW
Dawson
Feng
F
Yan
James M
JM
Davison
Scott A
SA
Houck
Xiaobo
X
Tang
Ning
N
Zheng
Michael B
MB
Major
Randall T
RT
Moon
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000975:Antioxidants / Q000378:metabolism*; D001667:Binding, Competitive / Q000502:physiology; D041321:Chromosomes, Human, X / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; C471644:BTRC protein, human; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D012694:Serine