ABSTRACT

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 α-catenin levels determine whether YAP1-WWTR1/TAZ signaling will be increased or decreased after macroautophagy/autophagy inhibition/induction. CTNNA1/α-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 α-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.

摘要

YAP1-WWTR1/TAZ 转录辅助因子是细胞生长的关键决定因素，在许多癌症中受到干扰。以前的研究报道了在不同情况下自噬扰动后 YAP1-WWTR1/TAZ 活动的不同反应。最近，我们发现 α-连环蛋白水平决定了在巨自噬/自噬抑制/诱导后 YAP1-WWTR1/TAZ 信号传导是否会增加或减少。CTNNA1/α-catenin 可以作为该通路的开关，因为它是自噬底物和 YAP1-WWTR1/TAZ 的负调节剂。然而，YAP1-WWTR1/TAZ 也被自噬直接降解，并且存在 YAP1-WWTR1/TAZ 正向调节自噬的反馈回路。这些特征被整合到基于一组微分方程的数学数值模型中，以阐明在具有不同初始水平 α-连环蛋白 (CTNNA1) 的细胞中自噬扰动后不同时间点 YAP1-WWTR1/TAZ 活性的综合输出和 CTNNA3)。我们的理论和实验数据有助于理解细胞类型特异性和时间依赖性对自噬操作的反应，这些反应可能在许多情况下都相关，包括不同类型的癌症。