YAP/TAZ are essential for TGF-β2–mediated conjunctival fibrosis

Akiko Futakuchi, Toshihiro Inoue, Fan Yan Wei, Miyuki Inoue-Mochita, Tomokazu Fujimoto, Kazuhito Tomizawa, Hidenobu Tanihara

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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-β2–mediated conjunctival fibrosis. METHODS. Primary human conjunctival fibroblasts were treated with TGF-β2. 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-β2 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-β2-mediated phosphorylation and the nuclear translocation of Smad2/3. Furthermore, a YAP/TAZ inhibitor markedly suppressed TGF-β2-mediated fibrotic changes in conjunctival fibroblasts. CONCLUSIONS. YAP/TAZ acted as a molecular hub of TGF-β2 signaling in a cellular model of conjunctival fibrosis. Moreover, verteporfin, a YAP/TAZ inhibitor exerted potent antifibrosis effects by suppressing TGF-β2-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.

Original languageEnglish
Pages (from-to)3069-3078
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number7
DOIs
Publication statusPublished - Jun 1 2018
Externally publishedYes

Keywords

  • Fibrosis
  • Glaucoma
  • TGF-β
  • The Hippo pathway

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Futakuchi, A., Inoue, T., Wei, F. Y., Inoue-Mochita, M., Fujimoto, T., Tomizawa, K., & Tanihara, H. (2018). YAP/TAZ are essential for TGF-β2–mediated conjunctival fibrosis. Investigative Ophthalmology and Visual Science, 59(7), 3069-3078. https://doi.org/10.1167/iovs.18-24258