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.

肌成纤维细胞是导致纤维化组织机械刚度增加的主要细胞类型。已有文献证明，在刚性底物条件下，成肌纤维细胞分化需要TGF-β/ Smad轴。然而，在柔软的基质中驱动成肌纤维细胞分化的机制仍然未知。在这项研究中，我们证明了通过动力蛋白，是相关蛋白（YAP）和乙酰化微管的相互作用，一种微管运动蛋白驱动YAP在软基质中的核定位，进而增加了TGF-β1诱导的Smad转录活性。肌成纤维细胞分化。尽管在α-微管蛋白乙酰基转移酶1（α-TAT1）敲除细胞中正常发生Smad的磷酸化和核定位，但动力蛋白的药理和遗传学破坏仍会损害YAP的核易位并降低TGF-β1诱导的Smad活性。而且，CCl诱导的纤维化肝脏血管附近的成纤维样细胞中显着出现微管乙酰化。TGF-β受体抑制剂反而降低了_4次给药。结果，微管乙酰化的定量抑制可能被建议作为克服纤维化疾病的新目标。