TY  - JOUR
AU  - Liu, Kaijing
AU  - Wehling, Lilija
AU  - Wan, Shan
AU  - Weiler, Sofia M E
AU  - Tóth, Marcell
AU  - Ibberson, David
AU  - Marhenke, Silke
AU  - Ali, Adnan
AU  - Lam, Macrina
AU  - Guo, Te
AU  - Pinna, Federico
AU  - Pedrini, Fabiola
AU  - Damle-Vartak, Amruta
AU  - Dropmann, Anne
AU  - Rose, Fabian
AU  - Colucci, Silvia
AU  - Cheng, Wenxiang
AU  - Bissinger, Michaela
AU  - Schmitt, Jennifer
AU  - Birner, Patrizia
AU  - Poth, Tanja
AU  - Angel, Peter
AU  - Dooley, Steven
AU  - Muckenthaler, Martina U
AU  - Longerich, Thomas
AU  - Vogel, Arndt
AU  - Heikenwälder, Mathias
AU  - Schirmacher, Peter
AU  - Breuhahn, Kai
TI  - Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.
JO  - Cellular and molecular life sciences
VL  - 81
IS  - 1
SN  - 1420-682X
CY  - Cham (ZG)
PB  - Springer International Publishing AG
M1  - DKFZ-2024-00485
SP  - 115
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Mice
KW  - Endothelial Cells
KW  - Ligands
KW  - Liver
KW  - Hepatocytes
KW  - Cell Communication
KW  - Cholangiocyte (Other)
KW  - Endothelial cell (Other)
KW  - Hepatocyte (Other)
KW  - Hippo pathway (Other)
KW  - Kupffer cell (Other)
KW  - Liver damage (Other)
KW  - Proteomics (Other)
KW  - Single-cell analysis (Other)
KW  - TAZ (Other)
KW  - Ligands (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38436764
C2  - pmc:PMC10912141
DO  - DOI:10.1007/s00018-024-05126-1
UR  - https://inrepo02.dkfz.de/record/288814
ER  -