Autolysosomal [beta]-catenin degradation regulates Wnt-autophagy-p62 crosstalk

• Published in: The EMBO journal 2013-07, Vol.32 (13), p.1903
• Main Authors: Petherick, Katy J, Williams, Ann C, Lane, Jon D, Ordóñez-morán, Paloma, Huelsken, Joerg, Collard, Tracey J, Smartt, Helena Jm, Batson, Jennifer, Malik, Karim, Paraskeva, Chris, Greenhough, Alexander
• Format: Article
• Language: English
• Subjects: Angiogenesis; Autophagy; Cancer; Gene expression; Nutrients; Signaling
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.123

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