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PMID: 17636022 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2.

Molecular and cellular biology ·Vol. 27 ·No. 18 ·2007-09-00 ·Pages 6334-49

Sun Z, Zhang S, Chan JY, Zhang DD

Abstract

The transcription factor Nrf2 regulates cellular redox homeostasis. Under basal conditions, Keap1 recruits Nrf2 into the Cul3-containing E3 ubiquitin ligase complex for ubiquitin conjugation and subsequent proteasomal degradation. Oxidative stress triggers activation of Nrf2 through inhibition of E3 ubiquitin ligase activity, resulting in increased levels of Nrf2 and transcriptional activation of Nrf2-dependent genes. In this study, we identify Keap1 as a key postinduction repressor of Nrf2 and demonstrate that a nuclear export sequence (NES) in Keap1 is required for termination of Nrf2-antioxidant response element (ARE) signaling by escorting nuclear export of Nrf2. We provide evidence that ubiquitination of Nrf2 is carried out in the cytosol. Furthermore, we show that Keap1 nuclear translocation is independent of Nrf2 and the Nrf2-Keap1 complex does not bind the ARE. Collectively, our results suggest the following mechanism of postinduction repression: upon recovery of cellular redox homeostasis, Keap1 translocates into the nucleus to dissociate Nrf2 from the ARE. The Nrf2-Keap1 complex is then transported out of the nucleus by the NES in Keap1. Once in the cytoplasm, the Keap1-Nrf2 complex associates with the E3 ubiquitin ligase, resulting in degradation of Nrf2 and termination of the Nrf2 signaling pathway. Hence, postinduction repression of the Nrf2-mediated antioxidant response is controlled by the nuclear export function of Keap1 in alliance with the cytoplasmic ubiquitination and degradation machinery.

MeSH Terms
Active Transport, Cell Nucleus Animals Antioxidants/metabolism Breast Neoplasms/pathology COS Cells Cell Line, Tumor Cell Nucleus/metabolism Chlorocebus aethiops Chromatin Immunoprecipitation Female Fluorescent Antibody Technique, Direct Gene Expression Regulation Genes, Reporter Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Kelch-Like ECH-Associated Protein 1 Luciferases/metabolism Mice Models, Biological Mutation NF-E2-Related Factor 2/genetics,metabolism NIH 3T3 Cells Oxidation-Reduction Repressor Proteins/genetics,metabolism Transfection Ubiquitin/metabolism
Chemicals
Antioxidants Intracellular Signaling Peptides and Proteins KEAP1 protein, human Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 NFE2L2 protein, human Repressor Proteins Ubiquitin Luciferases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Sun Zheng
Department of Pharmacology and Toxicology, University of Arizona, 1703 East Mabel Street, Tucson, AZ 85721, USA.
Zhang Shirley
Chan Jefferson Y
Zhang Donna D
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00630-07
Published
2007-09-00
Epub
2007-00-16
Pages
6334-49
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2099624
Subset
IM
Grants
NIEHS NIH HHS · R01 ES015010 · United States
NIEHS NIH HHS · 1 R01 ES015010-01 · United States
External Links
PubMed source DOI: 10.1128/MCB.00630-07 PMC Full Text View journal details
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