Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction

TLDR

Autophagy converges with YAP/TAZ transcriptional regulators, which are key to cell plasticity in tissue regeneration and cancer, partly mediated by the YAP/TAZ target Armus, a RAB‑GAP family protein. YAP/TAZ transcriptionally regulate autophagosome‑lysosome fusion, and mechanical cues from the ECM modulate autophagy efficiency, a link essential for YAP‑driven reprogramming of normal and benign tumor cells into stem‑like or cancer stem cells, coupling nuclear reprogramming with autophagy‑mediated cytoplasmic restructuring.

Abstract

Significance We describe the convergence of autophagy with YAP/TAZ, 2 highly related transcriptional regulators playing essential roles in cell plasticity for tissue regeneration and cancer. We show that a key event in autophagy, the fusion of autophagosomal vesicles with lysosomes, is transcriptionally regulated by YAP/TAZ. At least in part, this is mediated by the YAP/TAZ target Armus, a protein of the RAB-GAP family. Consistently with YAP/TAZ being patterned by mechanical signals, we found that cellular mechanics, dictated by the physical properties of the ECM, potently regulate autophagy efficiency. The connection described here is crucial for YAP-mediated reprogramming of normal cells into stem-like cells and of benign tumor cells in cancer stem cells. Thus, nuclear reprogramming must go hand in hand with autophagy-mediated cytoplasmic restructuring.