Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation

被引：21

作者：

You, Eunae ^{[1
]}

Ko, Panseon ^{[1
]}

Jeong, Jangho ^{[1
]}

Keum, Seula ^{[1
]}

Kim, Jung-Woong ^{[1
]}

Seo, Young-Jin ^{[1
]}

Song, Woo Keun ^{[2
]}

Rhee, Sangmyung ^{[1
]}

机构：

[1] Chung Ang Univ, Dept Life Sci, Seoul 06974, South Korea

[2] Gwangju Inst Sci & Technol, Sch Life Sci, Bio Imaging & Cell Logist Res Ctr, 123 Cheomdangwagi Ro, Gwangju 61005, South Korea

来源：

CELLULAR AND MOLECULAR LIFE SCIENCES | 2020年 / 77卷 / 20期

基金：

新加坡国家研究基金会;

关键词：

Myofibroblast; TGF-beta; 1; ECM stiffness; Microtubule acetylation; Liver fibrosis; YAP; Smad; HEPATIC STELLATE CELLS; SMOOTH-MUSCLE; MYOFIBROBLAST DIFFERENTIATION; GENE-EXPRESSION; FIBROSIS; YAP; TRANSPORT; IMPORT; PHOSPHORYLATION; MAINTENANCE;

D O I：

10.1007/s00018-019-03412-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-beta/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-beta 1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-beta 1-induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in alpha-tubulin acetyltransferase 1 (alpha-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl(4)administration, which was conversely decreased by TGF-beta receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases.

引用

页码：4143 / 4161

页数：19

共 41 条

[41] S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-B-dependent pathways
Xu, X.
Chen, H.
Zhu, X.
Ma, Y.
Liu, Q.
Xue, Y.
Chu, H.
Wu, W.
Wang, J.
Zou, H.
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2013, 173 (03): : 523 - 535

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