Autolysosomal ß-catenin degradation regulates Wnt-autophagy-p62 crosstalk.

ABSTRACT

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