TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts.
TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts.
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DOI：
10.1038/srep42595
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发表时间：
2017-02-14
影响因子：
4.6
通讯作者：
Nagase T
中科院分区：
文献类型：
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作者：
Noguchi S;Saito A;Mikami Y;Urushiyama H;Horie M;Matsuzaki H;Takeshima H;Makita K;Miyashita N;Mitani A;Jo T;Yamauchi Y;Terasaki Y;Nagase T
具有PDZ结合基序（TAZ）的转录辅激活因子调节多种生物学过程。TAZ的核转位和激活受多种机制的调控，包括肌动蛋白细胞骨架和机械力。TAZ参与肺发育过程中的肺泡形成，并且TAZ杂合子小鼠对博来霉素诱导的肺纤维化具有抗性。在这项研究中，我们探讨了TAZ在特发性肺纤维化（IPF）的发病机制中的作用，通过人肺组织的组织学分析和细胞培养实验。TAZ在IPF患者的肺成纤维细胞灶中高度表达。TAZ控制培养的肺成纤维细胞中肌成纤维细胞标志物的表达、增殖、迁移和基质收缩。重要的是，肌动蛋白应力纤维和TAZ的核积累更明显时，培养在一个僵硬的基质，这表明一个反馈机制，以加速纤维化反应。基因表达谱显示TAZ介导的调节结缔组织生长因子（CTGF）和I型胶原。使用公开可用的转录组数据进一步评估TAZ调节的基因签名的临床相关性。这些结果表明，TAZ通过对肺成纤维细胞的多方面影响参与IPF的发病机制。
Transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes. Nuclear translocation and activation of TAZ are regulated by multiple mechanisms, including actin cytoskeleton and mechanical forces. TAZ is involved in lung alveolarization during lung development and Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. In this study, we explored the roles of TAZ in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through histological analyses of human lung tissues and cell culture experiments. TAZ was highly expressed in the fibroblastic foci of lungs from patients with IPF. TAZ controlled myofibroblast marker expression, proliferation, migration, and matrix contraction in cultured lung fibroblasts. Importantly, actin stress fibers and nuclear accumulation of TAZ were more evident when cultured on a stiff matrix, suggesting a feedback mechanism to accelerate fibrotic responses. Gene expression profiling revealed TAZ-mediated regulation of connective tissue growth factor (CTGF) and type I collagen. Clinical relevance of TAZ-regulated gene signature was further assessed using publicly available transcriptome data. These findings suggest that TAZ is involved in the pathogenesis of IPF through multifaceted effects on lung fibroblasts.