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Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk
Research output: Contribution to journal › Article (Academic Journal)
126 Citations (Scopus)
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.
Petherick, K. J., Williams, A. C., Lane, J. D., Ordóñez-Morán, P., Huelsken, J., Collard, T. J., Smartt, H. J., Batson, J., Malik, K., Paraskeva, C., & Greenhough, A. (2013). Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk. EMBO Journal, 32(13), 1903 - 1916. https://doi.org/10.1038/emboj.2013.123