| First Author | Petherick KJ | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 13 | Pages | 1903-16 |
| PubMed ID | 23736261 | Mgi Jnum | J:199090 |
| Mgi Id | MGI:5500836 | Doi | 10.1038/emboj.2013.123 |
| Citation | Petherick KJ, et al. (2013) Autolysosomal beta-catenin degradation regulates Wnt-autophagy-p62 crosstalk. EMBO J 32(13):1903-16 |
| abstractText | 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. |
