Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.
Cholangiocyte
Endothelial cell
Hepatocyte
Hippo pathway
Kupffer cell
Liver damage
Proteomics
Single-cell analysis
TAZ
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
04 Mar 2024
04 Mar 2024
Historique:
received:
31
07
2023
accepted:
30
12
2023
revised:
11
12
2023
medline:
4
3
2024
pubmed:
4
3
2024
entrez:
4
3
2024
Statut:
epublish
Résumé
The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.
Identifiants
pubmed: 38436764
doi: 10.1007/s00018-024-05126-1
pii: 10.1007/s00018-024-05126-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : 505755359
Organisme : Deutsche Forschungsgemeinschaft
ID : 314905040
Organisme : Deutsche Forschungsgemeinschaft
ID : FOR5146
Organisme : Chinese Scholarship Council
ID : 201606100068
Informations de copyright
© 2024. The Author(s).
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