α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation

Nat Commun. 2021 Mar 17;12(1):1703. doi: 10.1038/s41467-021-21882-1.

Abstract

The factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology*
  • Cells, Cultured
  • Epithelial Cells
  • Feedback, Physiological
  • Humans
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mutation
  • Protein Binding
  • Protein Interaction Domains and Motifs / genetics
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins
  • alpha Catenin / chemistry
  • alpha Catenin / genetics
  • alpha Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • alpha Catenin