title: Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk.
abstract: 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.
authors.affiliation: Cancer Research UK Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Petherick
authors.forename: Ann C
authors.initials: AC
authors.lastname: Williams
authors.forename: Jon D
authors.initials: JD
authors.lastname: Lane
authors.forename: Paloma
authors.initials: P
authors.lastname: Ordóñez-Morán
authors.forename: Joerg
authors.initials: J
authors.lastname: Huelsken
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Collard
authors.forename: Helena J M
authors.initials: HJ
authors.lastname: Smartt
authors.forename: Jennifer
authors.initials: J
authors.lastname: Batson
authors.forename: Karim
authors.initials: K
authors.lastname: Malik
authors.forename: Chris
authors.initials: C
authors.lastname: Paraskeva
authors.forename: Alexander
authors.initials: A
authors.lastname: Greenhough
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex