YAP/TAZ Are Essential for TGF-β2-Mediated Conjunctival Fibrosis
YAP/TAZ Are Essential for TGF-β2-Mediated Conjunctival Fibrosis
复制标题
YAP/TAZ对TGF-β2介导的结膜纤维化至关重要
DOI：
10.1167/iovs.18-24258
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发表时间：
2018-06-01
影响因子：
4.4
通讯作者：
Tanihara, Hidenobu
中科院分区：
文献类型：
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作者：
Futakuchi, Akiko;Inoue, Toshihiro;Tanihara, Hidenobu
PURPOSE. To investigate the roles of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), the major effector molecules of the Hippo pathway, in TGF beta 2-mediated conjunctival fibrosis.METHODS. Primary human conjunctival fibroblasts were treated with TGF-beta 2. The expression of YAP/TAZ was examined by Western blot analyses and immunocytochemistry. The expression of fibrotic proteins and genes were evaluated by Western blot analyses and quantitative real-time PCR, respectively. The effects of YAP/TAZ on fibrotic changes were examined by knockdown experiments and the YAP/TAZ inhibitor, verteporfin.RESULTS. TGF-beta 2 stabilized YAP/TAZ and subsequently activated Smad2/3, which led to the transcription of fibrotic genes in human primary conjunctival fibroblasts. These fibrotic genes were differently regulated by YAP/TAZ. Notably, a-smooth muscle actin, fibronectin, collagen I, and collagen IV were primarily regulated by YAP. In contrast, CCN family proteins (CTGF and CYR61) depended on both YAP and TAZ. Mechanistically, YAP/TAZ were located in close proximity to Smad2/3, and in particular, YAP was required for TGF-beta 2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-beta 2-mediated fibrotic changes in conjunctival fibroblasts.CONCLUSIONS. YAP/TAZ acted as a molecular hub of TGF-beta 2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-beta 2-YAP/TAZ-Smad signaling. Our study highlights YAP/TAZ as essential regulators of conjunctival fibrosis and shows that inhibition of YAP/TAZ might potentially improve the outcomes of glaucoma filtration surgery.
