Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk

Petherick, Katy J.; Williams, Ann C.; Lane, Jon D.; Collard, Tracey J.; Petherick, Katy J; Williams, Ann C; Lane, Jon D; Collard, Tracey J; Ord��ez-Mor�n, Paloma; Huelsken, Joerg; Smartt, Helena Jm; Batson, Jennifer; Malik, Karim; Paraskeva, Chris; Greenhough, Alexander

Abstract

The Wnt/β-catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/β-catenin signalling pathway as a negative regulator of both basal and stress-induced autophagy. Manipulation of β-catenin expression levels in vitro and in vivo revealed that β-catenin suppresses autophagosome formation and directly represses p62/SQSTM1 (encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation β-catenin is selectively degraded via the formation of a β-catenin-LC3 complex, attenuating β-catenin/TCF-driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the β-catenin-LC3 complex is mediated by a W/YXXI/L motif and LC3-interacting region (LIR) in β-catenin, which is required for interaction with LC3 and non-proteasomal degradation of β-catenin. Thus, Wnt/β-catenin represses autophagy and p62 expression, while β-catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place β-catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy. © 2013 European Molecular Biology Organization.

• Journal Article Type: Article
• Acceptance Date: Apr 30, 2013
• Online Publication Date: Jun 4, 2013
• Publication Date: Jul 3, 2013
• Deposit Date: Feb 12, 2019
• Publicly Available Date: Feb 14, 2019
• Journal: EMBO Journal
• Print ISSN: 0261-4189
• Electronic ISSN: 1460-2075
• Publisher: EMBO Press
• Peer Reviewed: Peer Reviewed
• Volume: 32
• Issue: 13
• Pages: 1903-1916
• DOI: https://doi.org/10.1038/emboj.2013.123
• Keywords: autophagy, cancer, LC3, p62, Wnt/Β‐Catenin
• Public URL: https://uwe-repository.worktribe.com/output/930040
• Publisher URL: https://doi.org/10.1038/emboj.2013.123
• Additional Information: Additional Information : This is the accepted version of the paper. The final published version is available at https://doi.org/10.1038/emboj.2013.123
• Contract Date: Feb 12, 2019