4.8 Article

Light-responsive microRNA miR-211 targets Ezrin to modulate lysosomal biogenesis and retinal cell clearance

期刊

EMBO JOURNAL
卷 39, 期 8, 页码 -

出版社

WILEY
DOI: 10.15252/embj.2019102468

关键词

autophagy; Ezrin; miR-211; RPE; TFEB

资金

  1. BrightFocus Foundation [M2015317]
  2. Italian Telethon Foundation [TGM16CB6]
  3. European Research Council [694282, 311682]
  4. MIUR FIRB [RBAP11Z3YA]
  5. U.S. National Institutes of Health [R01-NS078072]
  6. Huffington Foundation
  7. Associazione Italiana per la Ricerca sul Cancro [21052, 22103]
  8. European Research Council (ERC) [311682, 694282] Funding Source: European Research Council (ERC)

向作者/读者索取更多资源

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 Ca2+ 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.

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