The roles of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) signaling in immune responses
Embargo Date
2026-11-24
OA Version
Citation
Abstract
The mechanical properties of tissues influence cellular structure and behavior, and defects in tissue mechanics are implicated in disease. Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ) function as key mechanosensors downstream of the Hippo pathway, transducing mechanical cues into cellular responses, including survival, proliferation, and differentiation. Growing evidence further highlights the roles of YAP and TAZ in immune modulation. In this study, we investigated the impact of YAP and TAZ on immune responses, focusing on epithelial cells in the lung and T cells recruited to tumors. With well-established roles of YAP and TAZ in governing epithelial cell fate decision in the lung, we explored how YAP/TAZ-regulated cell fate determination affects immune responses. Specifically, we examined the consequences of conditional deletion of YAP and TAZ in Scgb1a1+ airway club cells, which promotes goblet cell metaplasia throughout the lung epithelium. Using this model, we demonstrate that goblet cell metaplasia triggers global cellular responses throughout the lung, including in alveolar type II epithelial cells. Our findings show that goblet cell metaplasia initiates distinct responses by activating alveolar macrophages toward an M2-like phenotype, which leads to increased IL-1β production and further triggers inflammatory responses in alveolar type II cells. This study highlights the critical role of alveolar macrophages in mediating the communication between the airway and alveolar epithelium, establishing a novel link between airway epithelial remodeling and immune activation driven by YAP/TAZ depletion in secretory cells. We also investigated the influence of YAP and TAZ on T cell activity and anti-tumor responses within the cancer microenvironment. Our data indicate that YAP depletion in CD8+ T cells enhances T cell activation and improves anti-tumor immunity, highlighted by a significant increase in T cell infiltration into melanoma tumors. Further analysis revealed that YAP plays a key role in regulating T cell motility. YAP expression is induced by T cell receptor (TCR) activation, promoting cytoskeletal dynamics essential for modulating T cell motility and facilitating the release from TCR signaling. YAP-cKO CD8+ T cells exhibit reduced motility, resulting in prolonged interactions with TCR signals, which leads to enhanced T cell activation. Tumor-infiltrated YAP-cKO CD8+ T cells also demonstrate enhanced effector phenotypes. Additionally, we show that blocking the nuclear activity of the transcriptional enhanced associate domain (TEAD) transcription factors, which function as primary mediators of YAP/TAZ-mediated gene expression, impairs CD8+ T cell motility, underscoring the importance of YAP's nuclear function in modulating T cell behavior. Together, these studies highlight YAP/TAZ as key regulators of immune responses in both immune and non-immune cells. The findings presented in this thesis offer novel insights into the molecular mechanisms driving pulmonary inflammation and immune cell behavior regulated by YAP/TAZ.
Description
2025