Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk

EMBO J. 2013 Jul 3;32(13):1903-16. doi: 10.1038/emboj.2013.123. Epub 2013 Jun 4.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Autophagy*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoenzyme Techniques
  • Leukocyte Immunoglobulin-like Receptor B1
  • Lysosomes / metabolism*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Phagosomes / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequestosome-1 Protein
  • Transcription Factor 4
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • LILRB1 protein, human
  • Leukocyte Immunoglobulin-like Receptor B1
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Recombinant Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Proteasome Endopeptidase Complex