Airway secretory cell fate conversion via YAP‐mTORC1‐dependent essential amino acid metabolism

Abstract

Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular mechanisms governing these processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells, which subsequently lose their cellular identity and acquire squamous alveolar type 1 (AT1) fate in the lung. This cell fate conversion is mediated via distinctive transitional cell states of damage-associated transient progenitors (DATPs), recently shown to emerge during injury repair in mouse and human lungs. We further describe a YAP/TAZ signaling cascade to be integral for the fate conversion of secretory cells into AT1 fate, by modulating mTORC1/ATF4-mediated amino acid metabolism in vivo. Importantly, we observed aberrant activation of the YAP/TAZ-mTORC1-ATF4 axis in the altered airway epithelium of bronchiolitis obliterans syndrome, including substantial emergence of DATPs and AT1 cells with severe pulmonary fibrosis. Genetic and pharmacologic inhibition of mTORC1 activity suppresses lineage alteration and subepithelial fibrosis driven by YAP/TAZ activation, proposing a potential therapeutic target for human fibrotic lung diseases.

TRIB3 Mediates Fibroblast Activation and Fibrosis though Interaction with ATF4 in IPF

“…For instance, ATF4 is an important regulator of metabolic reprogramming in myofibroblasts [ 29 ]. In fact, TRIB3 is a target of CHOP/ATF4; when up-regulating ATF4 expression, the level of TRIB3 was markedly increased [ 16 , 34 ]. Several studies have shown that TRIB3 interacts with ATF4 and inhibits ATF4 transcription activity [ 21 , 22 , 23 ].…”

Functional and clinical characteristics of focal adhesion kinases in cancer progression

“…FAK stimulates PI3K/Akt signaling, whereas PI3K/Akt activation increases the levels of glutamine and its synthetase ( Van Der Vos et al, 2012 ). The YAP/TAZ pathway plays an important role in amino acid metabolic reprogramming ( Jeon et al, 2022 ), and FAK/Src signaling has been shown to mediate the activation of YAP/TAZ signaling in tumor cells ( Totaro et al, 2018 ; Ma et al, 2020 ). However, there are still questions regarding the specific mechanisms of FAK in amino acid metabolic reprogramming, such as whether it affects the expression of key enzymes and whether there are key signaling pathways.…”

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

“…In mouse lungs, continuous activation of YAP/TAZ induces the mTOR-ATF4 signaling pathway and leads to changes in the cell fate and identity of secretory airway cells and their conversion into squamous AT1-like cells [ 102 ]. In human bronchial epithelial cells (HBEC3s) an active interaction was found between YAP and mTOR/PI3K/AKT pathway, resulting to increased cell proliferation, migration and polarity, that potentially contribute to development of the idiopathic pulmonary fibrosis [ 72 ].…”