Caveolin1 and YAP drive mechanically induced mesothelial to mesenchymal transition and fibrosis.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Caveolin 1
/ metabolism
Caveolins
/ metabolism
Disease Models, Animal
Epithelial Cells
/ metabolism
Epithelial-Mesenchymal Transition
/ genetics
Female
Humans
Male
Mice
Mice, Inbred C57BL
Peritoneal Dialysis
/ methods
Peritoneal Fibrosis
/ genetics
Peritoneum
/ metabolism
Signal Transduction
/ drug effects
Smad3 Protein
/ metabolism
Tissue Adhesions
/ metabolism
Transcription Factors
/ metabolism
Transforming Growth Factor beta1
/ metabolism
YAP-Signaling Proteins
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
03 08 2020
03 08 2020
Historique:
received:
26
11
2019
accepted:
13
07
2020
revised:
10
07
2020
entrez:
20
8
2020
pubmed:
20
8
2020
medline:
13
4
2021
Statut:
epublish
Résumé
Despite their emerging relevance to fully understand disease pathogenesis, we have as yet a poor understanding as to how biomechanical signals are integrated with specific biochemical pathways to determine cell behaviour. Mesothelial-to-mesenchymal transition (MMT) markers colocalized with TGF-β1-dependent signaling and yes-associated protein (YAP) activation across biopsies from different pathologies exhibiting peritoneal fibrosis, supporting mechanotransduction as a central driving component of these class of fibrotic lesions and its crosstalk with specific signaling pathways. Transcriptome and proteome profiling of the response of mesothelial cells (MCs) to linear cyclic stretch revealed molecular changes compatible with bona fide MMT, which (i) overlapped with established YAP target gene subsets, and were largely dependent on endogenous TGF-β1 signaling. Importantly, TGF-β1 blockade blunts the transcriptional upregulation of these gene signatures, but not the mechanical activation and nuclear translocation of YAP per se. We studied the role therein of caveolin-1 (CAV1), a plasma membrane mechanotransducer. Exposure of CAV1-deficient MCs to cyclic stretch led to a robust upregulation of MMT-related gene programs, which was blunted upon TGF-β1 inhibition. Conversely, CAV1 depletion enhanced both TGF-β1 and TGFBRI expression, whereas its re-expression blunted mechanical stretching-induced MMT. CAV1 genetic deficiency exacerbated MMT and adhesion formation in an experimental murine model of peritoneal ischaemic buttons. Taken together, these results support that CAV1-YAP/TAZ fine-tune the fibrotic response through the modulation of MMT, onto which TGF-β1-dependent signaling coordinately converges. Our findings reveal a cooperation between biomechanical and biochemical signals in the triggering of MMT, representing a novel potential opportunity to intervene mechanically induced disorders coursing with peritoneal fibrosis, such as post-surgical adhesions.
Identifiants
pubmed: 32811813
doi: 10.1038/s41419-020-02822-1
pii: 10.1038/s41419-020-02822-1
pmc: PMC7435273
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CAV1 protein, human
0
Caveolin 1
0
Caveolins
0
Smad3 Protein
0
Transcription Factors
0
Transforming Growth Factor beta1
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
647Références
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