Myung-Gok Eye Research Institute, Konyang University, 158 Gwanjeodong-ro, Seo-gu, Daejeon, 35365, South Korea.
Department of Medical Science, Konyang University, 158 Gwanjeodong-ro, Seo-gu, Daejeon, 35365, South Korea.
Exp Mol Med. 2020 Jun;52(6):951-962. doi: 10.1038/s12276-020-0446-5. Epub 2020 Jun 12.
Corneal wound healing is essential for the maintenance of corneal integrity and transparency and involves a series of physiological processes that depend on the proliferation of epithelial cells. However, the molecular mechanisms that control corneal epithelial cell proliferation are poorly understood. Here, we show that Sestrin2, a stress-inducible protein, is downregulated in the corneal epithelium during wound healing and that the proliferation of epithelial basal cells is enhanced in Sestrin2-deficient mice. We also show that YAP, a major downstream effector of the Hippo signaling pathway, regulates cell proliferation during corneal epithelial wound repair and that Sestrin2 suppresses its activity. Moreover, increased levels of reactive oxygen species in the Sestrin2-deficient corneal epithelium promote the nuclear localization and dephosphorylation of YAP, activating it to enhance the proliferation of corneal epithelial cells. These results reveal that Sestrin2 is a negative regulator of YAP, which regulates the proliferative capacity of basal epithelial cells, and may serve as a potential therapeutic target for corneal epithelial damage.
角膜伤口愈合对于维持角膜完整性和透明度至关重要，涉及一系列依赖于上皮细胞增殖的生理过程。然而，控制角膜上皮细胞增殖的分子机制还知之甚少。在这里，我们表明，应激诱导蛋白 Sestrin2 在伤口愈合过程中角膜上皮细胞中下调，并且 Sestrin2 缺陷型小鼠的上皮基底层细胞增殖增强。我们还表明，Hippo 信号通路的主要下游效应物 YAP 调节角膜上皮伤口修复过程中的细胞增殖，并且 Sestrin2 抑制其活性。此外，Sestrin2 缺陷型角膜上皮中活性氧水平的增加促进 YAP 的核定位和去磷酸化，激活 YAP 以增强角膜上皮细胞的增殖。这些结果表明，Sestrin2 是 YAP 的负调节剂，调节基底层上皮细胞的增殖能力，并且可能成为角膜上皮损伤的潜在治疗靶点。
