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

Background: Autophagy is an intracellular lysosomal degradation pathway implicated in many diseases, but there are currently no specific autophagy inhibitors.Results: Small molecule inhibition of ULK1, the upstream autophagy initiating kinase, blocks autophagosome initiation and maturation.Conclusion: ULK1 plays a role in autophagosome maturation as well as initiation.Significance: ULK1 can be targeted to block autophagy for disease therapy.

In Fig. 1A, the molecular structures of the compounds for MRT67307 and MRT68921 were mistakenly switched. The corrected figure is shown below. This correction does not affect the interpretation of the results or conclusions of this work.