Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27705.
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, NC 27705
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2021942118.
Activation of autophagy is one of the responses elicited by high intraocular pressure (IOP) and mechanical stretch in trabecular meshwork (TM) cells. However, the mechanosensor and the molecular mechanisms by which autophagy is induced by mechanical stretch in these or other cell types is largely unknown. Here, we have investigated the mechanosensor and downstream signaling pathway that regulate cyclic mechanical stretch (CMS)-induced autophagy in TM cells. We report that primary cilia act as a mechanosensor for CMS-induced autophagy and identified a cross-regulatory talk between AKT1 and noncanonical SMAD2/3 signaling as critical components of primary cilia-mediated activation of autophagy by mechanical stretch. Furthermore, we demonstrated the physiological significance of our findings in ex vivo perfused eyes. Removal of primary cilia disrupted the homeostatic IOP compensatory response and prevented the increase in LC3-II protein levels in response to elevated pressure challenge, strongly supporting a role of primary cilia-mediated autophagy in regulating IOP homeostasis.
自噬的激活是眼内压（IOP）升高和小梁网（TM）细胞机械拉伸引起的反应之一。然而，机械感受器以及机械拉伸在这些或其他细胞类型中诱导自噬的分子机制在很大程度上尚不清楚。在这里，我们研究了调节 TM 细胞中环式机械拉伸（CMS）诱导自噬的机械感受器和下游信号通路。我们报告说，初级纤毛作为 CMS 诱导自噬的机械感受器，并确定 AKT1 和非经典 SMAD2/3 信号之间的交叉调节对话作为机械拉伸介导的自噬的初级纤毛激活的关键组成部分。此外，我们在离体灌注的眼睛中证明了我们发现的生理意义。去除初级纤毛会破坏内稳态 IOP 代偿反应，并阻止 LC3-II 蛋白水平在压力升高时升高，这强烈支持初级纤毛介导的自噬在调节 IOP 动态平衡中的作用。
