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

Mariana Pavel, So Jung Park, Rebecca A. Frake, Sung Min Son, Marco M. Manni, Carla F. Bento, Maurizio Renna, Thomas Ricketts, Fiona M. Menzies, Radu Tanasa and David C. Rubinsztein ()
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Mariana Pavel: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
So Jung Park: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Rebecca A. Frake: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Sung Min Son: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Marco M. Manni: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Carla F. Bento: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Maurizio Renna: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Thomas Ricketts: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Fiona M. Menzies: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building
Radu Tanasa: Alexandru Ioan Cuza University of Iasi
David C. Rubinsztein: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21882-1

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