Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis

John Hayes; Sharadha Dayalan Naidu; Albena Dinkova-Kostova

doi:10.1016/j.tibs.2024.12.010

Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis

John Hayes (Lead / Corresponding author), Sharadha Dayalan Naidu, Albena Dinkova-Kostova (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.

Original language	English
Pages (from-to)	179-205
Number of pages	27
Journal	Trends in Biochemical Sciences
Volume	50
Issue number	3
DOIs	https://doi.org/10.1016/j.tibs.2024.12.010
Publication status	Published - 6 Mar 2025

Keywords

NRF2
KEAP1
redox switch
signaling
SQSTM1/p62
β-TrCP

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10.1016/j.tibs.2024.12.010Licence: CC BY

The Role of Nrf2 in the Tumour Microenvironment of IDH Wild-Type Glioma (Joint with University of Edinburgh)
Dinkova-Kostova, A. (Investigator)
Medical Research Council
1/11/22 → 31/10/25
Project: Research
Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis
Arthur, S. (Investigator), Dillon, J. (Investigator), Dinkova-Kostova, A. (Investigator), Hayes, J. (Investigator) & Henderson, C. (Investigator)
Medical Research Council
1/04/20 → 30/06/25
Project: Research

Cite this

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title = "Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis",

abstract = "Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.",

keywords = "NRF2, KEAP1, redox switch, signaling, SQSTM1/p62, β-TrCP",

author = "John Hayes and {Dayalan Naidu}, Sharadha and Albena Dinkova-Kostova",

year = "2025",

month = mar,

day = "6",

doi = "10.1016/j.tibs.2024.12.010",

language = "English",

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pages = "179--205",

journal = "Trends in Biochemical Sciences",

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TY - JOUR

T1 - Regulating Nrf2 activity

T2 - ubiquitin ligases and signaling molecules in redox homeostasis

AU - Hayes, John

AU - Dayalan Naidu, Sharadha

AU - Dinkova-Kostova, Albena

PY - 2025/3/6

Y1 - 2025/3/6

N2 - Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.

AB - Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3Keap1, CRL4DCAF11, SCFβ-TrCP, and Hrd1). CRL3Keap1 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors. Repression of Nrf2 by CRL3Keap1 is attenuated by SQSTM1/p62, and this is reinforced by phosphorylation of SQSTM1/p62. Repression by SCFβ-TrCP requires phosphorylation of Nrf2 by GSK3, the activity of which is inhibited by PKB/Akt and other kinases. We discuss how Nrf2 activity is controlled by the ubiquitin ligases under different circumstances. We also describe endogenous signaling molecules that inactivate CRL3Keap1 to alleviate stress and restore homeostasis.

KW - NRF2

KW - KEAP1

KW - redox switch

KW - signaling

KW - SQSTM1/p62

KW - β-TrCP

U2 - 10.1016/j.tibs.2024.12.010

DO - 10.1016/j.tibs.2024.12.010

M3 - Article

C2 - 39875264

SN - 0968-0004

VL - 50

SP - 179

EP - 205

JO - Trends in Biochemical Sciences

JF - Trends in Biochemical Sciences

IS - 3

ER -

Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis

Abstract

Keywords

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Projects

The Role of Nrf2 in the Tumour Microenvironment of IDH Wild-Type Glioma (Joint with University of Edinburgh)

Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis

Cite this