Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation.
Cell Mol Life Sci
; 77(20): 4143-4161, 2020 Oct.
Article
en En
| MEDLINE
| ID: mdl-31912196
ABSTRACT
Myofibroblasts are the major cell type that is responsible for increase in the mechanical stiffness in fibrotic tissues. It has well documented that the TGF-ß/Smad axis is required for myofibroblast differentiation under the rigid substrate condition. However, the mechanism driving myofibroblast differentiation in soft substrates remains unknown. In this research, we demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via dynein, a microtubule motor protein drives nuclear localization of YAP in the soft matrix, which in turn increased TGF-ß1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-ß1-induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in α-tubulin acetyltransferase 1 (α-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl4 administration, which was conversely decreased by TGF-ß receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Núcleo Celular
/
Dineínas
/
Proteínas de Ciclo Celular
/
Transporte de Proteínas
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Proteínas Adaptadoras Transductoras de Señales
/
Fibroblastos
/
Microtúbulos
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Cell Mol Life Sci
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2020
Tipo del documento:
Article