Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes

Rada, Patricia, Rojo, Ana I., Offergeld, Anika ORCID: https://orcid.org/0000-0001-8916-2505, Feng, Gui Jie, Velasco-Martín, Juan P., González-Sancho, José Manuel, Valverde, Ángela M., Dale, Trevor Clive ORCID: https://orcid.org/0000-0002-4880-9963, Regadera, Javier and Cuadrado, Antonio 2015. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes. Antioxidants & Redox Signaling 22 (7) , pp. 555-571. 10.1089/ars.2014.6040

[thumbnail of ars.2014.6040 (1).pdf]
Preview
PDF - Published Version
Available under License Creative Commons Attribution Non-commercial.

Download (1MB) | Preview

Abstract

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of oxidant and xenobiotic metabolism, but it is unknown how it is regulated to provide basal expression of this defense system. Here, we studied the putative connection between NRF2 and the canonical WNT pathway, which modulates hepatocyte metabolism. Results: WNT-3A increased the levels of NRF2 and its transcriptional signature in mouse hepatocytes and HEK293T cells. The use of short interfering RNAs in hepatocytes and mouse embryonic fibroblasts which are deficient in the redox sensor Kelch-like ECH-associated protein 1 (KEAP1) indicated that WNT-3A activates NRF2 in a β-Catenin- and KEAP1-independent manner. WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/β-TrCP-dependent ubiquitination and proteasomal degradation. Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2. Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. The relevance of this novel pathway was assessed in mice with a conditional deletion of Axin1 in the liver, which showed upregulation of the NRF2 signature in hepatocytes and disruption of liver zonation of antioxidant metabolism. Innovation: NRF2 takes part in a protein complex with Axin1 that is regulated by the canonical WNT pathway. This new WNT-NRF2 axis controls the antioxidant metabolism of hepatocytes. Conclusion: These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: Mary Ann Liebert
ISSN: 1523-0864
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 21 October 2014
Last Modified: 29 Jun 2023 08:44
URI: https://orca.cardiff.ac.uk/id/eprint/71289

Citation Data

Cited 39 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics