Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast acti
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Dynein‑mediated nuclear translocation of yes‑associated protein through microtubule acetylation controls fibroblast activation Eunae You1 · Panseon Ko1 · Jangho Jeong1 · Seula Keum1 · Jung‑Woong Kim1 · Young‑Jin Seo1 · Woo Keun Song2 · Sangmyung Rhee1 Received: 12 July 2019 / Revised: 27 November 2019 / Accepted: 4 December 2019 © Springer Nature Switzerland AG 2020
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-β/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-β1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-β1-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-β receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases. Keywords Myofibroblast · TGF-β1 · ECM stiffness · Microtubule acetylation · Liver fibrosis · YAP · Smad Abbreviations ECM Extracellular matrix MEFs Mouse embryonic fibroblasts α-TAT1 α-Tubulin acetyltransferase 1 TGF-β1 Transforming growth factor beta1 α-SMA Alpha-smooth muscle actin EHNA Erythro-9-(2-hydroxy-3-nonyl)adenine FMC Floating matrix contraction SMC Stressed matrix contraction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03412-x) contains supplementary material, which is available to authorized users. * Woo Keun Song [email protected] * Sangmyung Rhee [email protected] 1
Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
Bio Imaging and Cell Logistics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi‑ro, Buk‑Gu, Gwangju 61005, Republic of Korea
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YAP Yes-associated protein CCl4 Cabon tetrachloride PTMs Post-translational modifications ICC Immunocytochemistry IHC Immunohistochemistry
Introduction Differentiation and phenotypical plasticity of cells are critically dependent on the nature of the cellular microenvironment [1, 2]. The cellular microenvironment is composed of various types of extracellular matrix (ECM) proteins, soluble gr
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