Shim Myoung Sup, Sim Ethan J, Betsch Kevin, Desikan Vaibhav, Su Chien-Chia, Pastor-Valverde Diego, Sun Yang, Liton Paloma B
Department of Ophthalmology, Duke Eye Center, Duke University, AERI Bldg, Office 4004, Erwin, Rd. Box 3802, Durham, NC, 27713, USA.
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, USA.
Cell Mol Life Sci. 2025 Feb 22;82(1):82. doi: 10.1007/s00018-025-05615-x.
Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, a leading cause of irreversible blindness worldwide. IOP homeostasis is maintained through a balance between aqueous humor production and its drainage through the trabecular meshwork (TM)/Schlemm's Canal (SC) outflow pathway. Prior studies by our laboratory reported a key role of mechanical forces and primary cilia (PC)-dependent stretch-induced autophagy in IOP homeostasis. However, the precise mechanism regulating this process remains elusive. In this study, we investigated the upstream signaling pathway orchestrating autophagy activation during cyclic mechanical stretch (CMS) in primary cultured human TM cells, using biochemical and cell biological analyses. Our results indicate that TM cells express catalytic subunits of class IA PI3Ks (PIK3CA, B, and D), and that inhibition of class IA isoforms, but not class II and III, significantly prevent CMS-induced autophagy. Importantly, PIK3CA was found to localize in the PC. Furthermore, we identified a coordinated action of Class IA PI3Ks along INPP4A/B, a 4' inositol phosphatase, responsible for the formation of PI(3,4)P and PI(3)P and stretch-induced autophagy in TM cells. These findings contribute to a deeper understanding of the molecular mechanisms underlying IOP homeostasis.
眼内压升高是青光眼的主要危险因素，青光眼是全球不可逆失明的主要原因。眼内压稳态通过房水生成与通过小梁网（TM）/施莱姆管（SC）流出途径的引流之间的平衡来维持。我们实验室先前的研究报道了机械力和初级纤毛（PC）依赖性拉伸诱导的自噬在眼内压稳态中的关键作用。然而，调节这一过程的精确机制仍然难以捉摸。在本研究中，我们使用生化和细胞生物学分析方法，研究了在原代培养的人小梁网细胞中，在周期性机械拉伸（CMS）过程中协调自噬激活的上游信号通路。我们的结果表明，小梁网细胞表达IA类磷脂酰肌醇-3激酶（PI3K）的催化亚基（PIK3CA、B和D），并且抑制IA类亚型而非II类和III类，可显著阻止CMS诱导的自噬。重要的是，发现PIK3CA定位于初级纤毛。此外，我们确定了IA类PI3K与INPP4A/B（一种4' 肌醇磷酸酶）的协同作用，INPP4A/B负责PI(3,4)P和PI(3)P的形成以及小梁网细胞中的拉伸诱导自噬。这些发现有助于更深入地理解眼内压稳态的分子机制。
