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

Mariana Pavel1,2, So Jung Park1,3, Rebecca A Frake1

  • 1Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, UK.

Nature Communications
|March 18, 2021
PubMed

Insights

Cellular identity is regulated by feedback loops involving autophagy and α-catenins. Autophagy perturbation impacts YAP/TAZ signaling differently based on α-catenin levels, revealing how protein intermediaries dictate cellular responses.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cellular identity regulation is crucial for understanding health, disease transitions, and therapeutic responses.
  • Autophagy modulation presents context-dependent effects on YAP/TAZ signaling, acting as co-transcriptional regulators of the Hippo pathway.
  • Conflicting literature exists regarding autophagy's role in YAP/TAZ activation or inhibition.

Purpose of the Study:

  • To investigate the mechanisms underlying the apparently contradictory effects of autophagy perturbation on YAP/TAZ signaling.
  • To elucidate the role of α-catenins in mediating the relationship between autophagy and YAP/TAZ activity.
  • To understand how feedback loops contribute to post-transcriptional determination of cell identity.

Main Methods:

  • Experimental confirmation of autophagy perturbation effects on YAP/TAZ signaling across different cell types.
  • Analysis of the feedback loop involving autophagy, α-catenins, and YAP/TAZ.
  • Quantification of α-catenin levels and their correlation with autophagy and YAP/TAZ activity.

Main Results:

  • Autophagy perturbation elicits opposing responses in YAP/TAZ transcriptional signaling depending on the cell type.
  • A feedback loop was identified where autophagy negatively regulates α-catenin levels, which inhibit YAP/TAZ; YAP/TAZ positively regulate autophagy.
  • High basal α-catenin levels promote autophagy induction to activate YAP/TAZ, whereas low α-catenin levels lead to YAP/TAZ activation upon autophagy inhibition.

Conclusions:

  • The study resolves contradictory findings by demonstrating a feedback mechanism regulating YAP/TAZ signaling via α-catenins.
  • Cellular identity determination is influenced by post-transcriptional regulation and feedback loops.
  • Intermediary protein levels, specifically α-catenins, dictate the direction of cellular response to perturbations.

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