Airway secretory cell fate conversion via YAP‐mTORC1‐dependent essential amino acid metabolism
Authors
Jeon, Hae Yon
Choi, Jinwook
Yi, Kijong
Kang, Ju‐Gyeong
Publication Date
2022-04-19Journal Title
The EMBO Journal
ISSN
0261-4189
Publisher
EMBO
Language
en
Type
Article
This Version
AO
VoR
Metadata
Show full item recordCitation
Jeon, H. Y., Choi, J., Kraaier, L., Kim, Y. H., Eisenbarth, D., Yi, K., Kang, J., et al. (2022). Airway secretory cell fate conversion via YAP‐mTORC1‐dependent essential amino acid metabolism. The EMBO Journal https://doi.org/10.15252/embj.2021109365
Description
Funder: Suh Kyungbae Foundation
Abstract
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.
Keywords
EMBO21, EMBO35, EMBO37, Article, Articles, Damage‐Associated Transient Progenitors, essential amino acid metabolism, Hippo‐YAP signaling, mTORC1‐ATF4 axis, pulmonary fibrosis and bronchiolitis obliterans
Sponsorship
EC|H2020|H2020 Priority Excellent Science | H2020 European Research Council (ERC) (679411)
Wellcome Trust (WT) (107633/Z/15/Z)
National Research Foundation of Korea (NRF) (NRF‐2020‐2048437, NRF‐2014‐1020336, NRF‐2020‐2079551)
Embargo Lift Date
2100-01-01
Identifiers
embj2021109365
External DOI: https://doi.org/10.15252/embj.2021109365
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334961
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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