Telethon Institute of Genetics and Medicine, Pozzuoli (Naples), Italy.
Department of Translational Medicine, University of Naples Federico II, Naples, Italy.
EMBO J. 2020 Apr 15;39(8):e102468. doi: 10.15252/embj.2019102468. Epub 2020 Mar 10.
Vertebrate vision relies on the daily phagocytosis and lysosomal degradation of photoreceptor outer segments (POS) within the retinal pigment epithelium (RPE). However, how these events are controlled by light is largely unknown. Here, we show that the light-responsive miR-211 controls lysosomal biogenesis at the beginning of light-dark transitions in the RPE by targeting Ezrin, a cytoskeleton-associated protein essential for the regulation of calcium homeostasis. miR-211-mediated down-regulation of Ezrin leads to Ca influx resulting in the activation of calcineurin, which in turn activates TFEB, the master regulator of lysosomal biogenesis. Light-mediated induction of lysosomal biogenesis and function is impaired in the RPE from miR-211 mice that show severely compromised vision. Pharmacological restoration of lysosomal biogenesis through Ezrin inhibition rescued the miR-211 phenotype, pointing to a new therapeutic target to counteract retinal degeneration associated with lysosomal dysfunction.
脊椎动物的视觉依赖于视网膜色素上皮（RPE）中光感受器外节（POS）的每日吞噬作用和溶酶体降解。然而，光线如何控制这些事件在很大程度上尚不清楚。在这里，我们表明，光响应的 miR-211 通过靶向 Ezrin（一种细胞骨架相关蛋白，对于钙稳态的调节至关重要）来控制光暗转换开始时 RPE 中的溶酶体生物发生。miR-211 介导的 Ezrin 下调导致 Ca 内流，从而激活钙调神经磷酸酶，进而激活溶酶体生物发生的主调节因子 TFEB。miR-211 小鼠的 RPE 中，光介导的溶酶体生物发生和功能的诱导受损，表现出严重的视力障碍。通过 Ezrin 抑制进行溶酶体生物发生的药理学恢复挽救了 miR-211 表型，为对抗与溶酶体功能障碍相关的视网膜变性提供了新的治疗靶点。
