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

Katy J Petherick, Ann C Williams, Jon D Lane, Paloma Ordóñez-Morán, Joerg Huelsken, Tracey J Collard, Helena Jm Smartt, Jennifer Batson, Karim Malik, Christos Paraskeva, Alexander Greenhough

Research output: Contribution to journalArticle (Academic Journal)

123 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1903 - 1916
Number of pages14
JournalEMBO Journal
Volume32
Issue number13
DOIs
Publication statusPublished - 4 Jun 2013

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