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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Autophagy*
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Blotting, Western
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Chromatin Immunoprecipitation
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology*
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Fluorescent Antibody Technique
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Humans
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Immunoenzyme Techniques
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Leukocyte Immunoglobulin-like Receptor B1
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Lysosomes / metabolism*
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Phagosomes / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequestosome-1 Protein
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / antagonists & inhibitors
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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LILRB1 protein, human
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Leukocyte Immunoglobulin-like Receptor B1
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MAP1LC3A protein, human
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Microtubule-Associated Proteins
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Immunologic
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Recombinant Proteins
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SQSTM1 protein, human
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Sequestosome-1 Protein
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Wnt Proteins
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beta Catenin
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Proteasome Endopeptidase Complex