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

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.

The complexity of biological control systems: An autophagy case study

“…In cells with high basal α‐catenin expression, a high feedback effect (of YAP1 controlling autophagy) will cause a lesser reduction in the YAP activity output upon autophagy compromise, but only at earlier time points. [ 26,30 ] For cancer cells, [ 38 ] the typically heightened autophagy flux is expected to cause an increase in the magnitude of the observed effect only for the low α‐catenin cases. A second general observation could be made at this point: the feedback paths control the magnitude of the investigated effects in a time‐dependent manner.…”

“…The tight interconnections between autophagy and various signalling routes ultimately dictate cell fate and often serve as the main control systems that define cell identity. [ 5,26 ]…”

“…Consequently, autophagy positively regulates YAP1 protein levels and activity in a number of cell lines with high basal levels of α‐catenins, like the non‐malignant mammary epithelial (MFC10A) cells, human embryonic kidney (HEK293T) cells, human cervical epithelium (HeLa) cells, primary mouse embryonic fibroblasts (pMEFs) or primary mammary epithelial cells (pMECs). [ 26,30 ] On the other hand, previous studies have identified that Yap1 itself is an autophagy substrate (independently of p62 expression), and have further shown, using in vivo models (Atg7KO mice) or hepatocyte cell lines (Atg7‐deficient murine AML12, or human THLE5B), that autophagy negatively impacts Yap1 activity, as Atg7‐deficiency leads to the accumulation of active Yap1 that increases liver size, causing progenitor cell expansion with hepatocarcinogenesis. [ 31 ] This result was also confirmed by us using various hepatocyte cell lines (THLE2, HepG2, Huh7 cells) or non‐small cell lung cancer cells (A549 cells), as all these cells have a low basal protein expression of α‐catenins.…”

“…[ 31 ] This result was also confirmed by us using various hepatocyte cell lines (THLE2, HepG2, Huh7 cells) or non‐small cell lung cancer cells (A549 cells), as all these cells have a low basal protein expression of α‐catenins. [ 26,30 ] In other words, one may conclude that cells that have the capacity to bind a significant portion of the YAP1 pool by α‐catenins will respond to autophagy inhibition by reducing cell proliferation, size and migration capacities, while cells that have transcriptional changes or PTMs that overcome or lower this interaction will behave in completely opposite way, as the direct ability of autophagy to degrade YAP1 will be dominant: autophagy inhibition would activate YAP1 (Figure 1A). From a general perspective, one may summarise that the initial posttranslational status is crucial in defining the direction of response to any external/internal perturbation (of autophagy or other metabolic pathways).…”

“…To answer this question, we previously developed a mathematical model of three interconnected differential equations that describe the dynamics of the three key players (autophagy, YAP1 activity and α‐catenin levels) in a time‐dependent manner, starting from the three main constituent processes (Figure S1, Supporting Information): [ 26 ] i) autophagy positively modulates YAP1 activity by degrading its inhibitor, α‐catenin (so‐called positive forward path; the α‐catenin that accumulates upon autophagy inhibition interacts with YAP1 and sequesters it into the cytosoplasm); [ 27 ] ii) autophagy negatively modulates YAP1 activity by facilitating its direct degradation (so‐called negative forward path; active‐YAP1 accumulates upon autophagy inhibition); [ 31 ] iii) the feedback path of YAP1 positively controlling autophagy (by monitoring autophagosome formation, maturation, and fusion with lysosomes). [ 14,36 ] Thus, during autophagy inhibition, the rate of autophagy decrease is controlled by both the decay rate due to the applied perturbation (parameter c), [ 26,39 ] and the strength of the feedback path (parameter v Y ). The rate of YAP1 variation relies on the balance between the strengths of the two, positive (controlled by parameter r1, which defines the strength of the cytosolic‐sequestration rate of YAP1 by α‐catenins) and negative (controlled by parameter r2, which defines the strength of active‐YAP1 accumulation rate upon autophagy inhibition) forward paths , while the rate of α‐catenin accumulation depends on its degradation rate by autophagy (controlled by parameter r3).…”