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

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 modulate...

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Veröffentlicht in:Antioxidants & redox signaling 2015-03, Vol.22 (7), p.555-571
Hauptverfasser: Rada, Patricia, Rojo, Ana I, Offergeld, Anika, Feng, Gui Jie, Velasco-Martín, Juan P, González-Sancho, José Manuel, Valverde, Ángela M, Dale, Trevor, Regadera, Javier, Cuadrado, Antonio
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container_end_page 571
container_issue 7
container_start_page 555
container_title Antioxidants & redox signaling
container_volume 22
creator Rada, Patricia
Rojo, Ana I
Offergeld, Anika
Feng, Gui Jie
Velasco-Martín, Juan P
González-Sancho, José Manuel
Valverde, Ángela M
Dale, Trevor
Regadera, Javier
Cuadrado, Antonio
description 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. 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. 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. These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism.
doi_str_mv 10.1089/ars.2014.6040
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These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism.</description><subject>Animals</subject><subject>Antioxidants - metabolism</subject><subject>Axin Protein - genetics</subject><subject>Axin Protein - metabolism</subject><subject>Cell Line</subject><subject>Gene Knockdown Techniques</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Liver - cytology</subject><subject>Liver - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Original Research Communications</subject><subject>Wnt3A Protein - metabolism</subject><issn>1523-0864</issn><issn>1557-7716</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFLwzAUh4Mobk6PXqVHL93ykjZNL8IYToUxQSYePIS0SbdI29Qmk-2_t2NzuOTwAvl47_H7ELoFPATM05Fs3ZBgiIYMR_gM9SGOkzBJgJ3v3oSGmLOoh66c-8IYEwB8iXokppRBwvvo82O-COk4aPVyXUqvXSDrYLwxNYzmb1MS5LZqSr0J_Er6E8gbuzGqq0GlvcxsaVwVmDpY6UZ6m2876hpdFLJ0-uZQB-h9-riYPIez16eXyXgW5pQnPgSWpQkAjdIspamiTHOMFSgOqiBQsO7IlEnOmWJ5wVmiFSG55EUKiuGM0AF62Pdt1lmlVa5r38pSNK2pZLsVVhpx-lOblVjaHxHRLobuDtD9oUFrv9faeVEZl-uylLW2ayeAxXFMMO1iG6Bwj-atda7VxXEMYLETIjohYidE7IR0_N3_3Y70nwH6Cy3Ah2Q</recordid><startdate>20150301</startdate><enddate>20150301</enddate><creator>Rada, Patricia</creator><creator>Rojo, Ana I</creator><creator>Offergeld, Anika</creator><creator>Feng, Gui Jie</creator><creator>Velasco-Martín, Juan P</creator><creator>González-Sancho, José Manuel</creator><creator>Valverde, Ángela M</creator><creator>Dale, Trevor</creator><creator>Regadera, Javier</creator><creator>Cuadrado, Antonio</creator><general>Mary Ann Liebert, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150301</creationdate><title>WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes</title><author>Rada, Patricia ; 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subjects Animals
Antioxidants - metabolism
Axin Protein - genetics
Axin Protein - metabolism
Cell Line
Gene Knockdown Techniques
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Hepatocytes - metabolism
Humans
Liver - cytology
Liver - metabolism
Mice
Mice, Transgenic
Original Research Communications
Wnt3A Protein - metabolism
title WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes
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