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WDR23 regulates NRF2 independently of KEAP1
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WDR23 regulates NRF2 independently of KEAP1
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Journal Article
WDR23 regulates NRF2 independently of KEAP1
2017
Overview
Cellular adaptation to stress is essential to ensure organismal survival. NRF2/NFE2L2 is a key determinant of xenobiotic stress responses, and loss of negative regulation by the KEAP1-CUL3 proteasome system is implicated in several chemo- and radiation-resistant cancers. Advantageously using C. elegans alongside human cell culture models, we establish a new WDR23-DDB1-CUL4 regulatory axis for NRF2 activity that operates independently of the canonical KEAP1-CUL3 system. WDR23 binds the DIDLID sequence within the Neh2 domain of NRF2 to regulate its stability; this regulation is not dependent on the KEAP1-binding DLG or ETGE motifs. The C-terminal domain of WDR23 is highly conserved and involved in regulation of NRF2 by the DDB1-CUL4 complex. The addition of WDR23 increases cellular sensitivity to cytotoxic chemotherapeutic drugs and suppresses NRF2 in KEAP1-negative cancer cell lines. Together, our results identify WDR23 as an alternative regulator of NRF2 proteostasis and uncover a cellular pathway that regulates NRF2 activity and capacity for cytoprotection independently of KEAP1.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Amino Acid Motifs - genetics
/ Analysis
/ Animals
/ Bile
/ Biology
/ Caenorhabditis elegans - genetics
/ Caenorhabditis elegans Proteins - genetics
/ Caenorhabditis elegans Proteins - metabolism
/ Funding
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Genetics
/ Grants
/ Heart
/ Humans
/ Kelch-Like ECH-Associated Protein 1 - genetics
/ Kelch-Like ECH-Associated Protein 1 - metabolism
/ Lungs
/ Mutation
/ NF-E2-Related Factor 2 - genetics
/ NF-E2-Related Factor 2 - metabolism
/ Nuclei
/ Proteasome Endopeptidase Complex - genetics
/ Proteasome Endopeptidase Complex - metabolism
/ Proteins
/ Repressor Proteins - genetics
/ Repressor Proteins - metabolism
/ Research and Analysis Methods
/ Rodents
/ Studies
