Light‐responsive microRNA miR‐211 targets Ezrin to modulate lysosomal biogenesis and retinal cell clearance
- 10 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 39 (8), e102468
- https://doi.org/10.15252/embj.2019102468
Abstract
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.Keywords
Funding Information
- BrightFocus Foundation (M2015317)
- National Institutes of Health (R01‐NS078072)
- Associazione Italiana per la Ricerca sul Cancro (21052, 22103)
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