Cell type-specific YAP1-WWTR1/TAZ transcriptional responses after autophagy perturbations are determined by levels of α-catenins (CTNNA1 and CTNNA3)

The YAP1-WWTR1/TAZ transcription co-factors are key determinants of cell growth that are perturbed in many cancers. Previous studies have reported divergent responses in YAP1-WWTR1/TAZ activities after autophagy perturbations in different contexts. Recently, we identified that alpha-catenin levels determine whether YAP1-WWTR1/TAZ signaling will be increased or decreased after macroautophagy/autophagy inhibition/induction. CTNNA1/alpha-catenin can act as a switch in this pathway, as it is an autophagy substrate and a negative regulator of YAP1-WWTR1/TAZ. However, YAP1-WWTR1/TAZ are also directly degraded by autophagy and there is a feedback loop where YAP1-WWTR1/TAZ positively regulate autophagy. These features were integrated into a mathematical numerical model based on a set of differential equations in order to clarify the integrated output on YAP1-WWTR1/TAZ activity at different time-points after autophagy perturbation in cells with distinct initial levels of alpha-catenins (CTNNA1 and CTNNA3). Our theoretical and experimental data allow an understanding of cell-type specific and time-dependent responses to autophagy manipulations that may be relevant in many contexts, including different types of cancer.

Automated summary

The YAP1-WWTR1/TAZ transcription co-factors play a crucial role in cell growth and may be dysregulated in cancer. The study reveals that alpha-catenin levels act as a switch in determining the response of YAP1-WWTR1/TAZ signaling after autophagy perturbations, with a complex feedback loop between YAP1-WWTR1/TAZ and autophagy. The integration of experimental and theoretical data provides insights into cell-specific and time-dependent responses to autophagy manipulations, potentially relevant in various cancer contexts.