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

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 alpha -catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of alpha -catenins enable autophagy induction to positively regulate YAP/TAZ, while low alpha -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. Autophagy regulates multiple pathways including YAP/TAZ of the Hippo pathway, but precise mechanisms are unclear as autophagy may either activate or inhibit YAP/TAZ. Here, the authors show that autophagy can either activate or regulate YAP/TAZ via dynamic negative feedback loops involving alpha-catenin.

Automated summary

This study reveals that autophagy can have opposing effects on the regulation of YAP/TAZ, depending on cellular context, due to a negative feedback loop involving alpha-catenin.