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

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

SUBMITTER: Petherick KJ 

PROVIDER: S-EPMC3981178 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature