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

被引：29

作者：

Naso, Federica ^{[1
]}

Intartaglia, Daniela ^{[1
]}

Falanga, Danila ^{[1
]}

Soldati, Chiara ^{[1
]}

Polishchuk, Elena ^{[1
]}

Giamundo, Giuliana ^{[1
]}

Tiberi, Paola ^{[1
]}

Marrocco, Elena ^{[1
]}

Scudieri, Paolo ^{[1
]}

Di Malta, Chiara ^{[1
]}

Trapani, Ivana ^{[1
]}

Nusco, Edoardo ^{[1
]}

Salierno, Francesco Giuseppe ^{[1
]}

Surace, Enrico Maria ^{[1
,2
]}

Galietta, Luis J., V ^{[1
,2
]}

Banfi, Sandro ^{[1
,3
]}

Auricchio, Alberto ^{[1
,2
]}

Ballabio, Andrea ^{[1
,2
,4
,5
]}

Medina, Diego Luis ^{[1
]}

Conte, Ivan ^{[1
,6
]}

机构：

[1] Telethon Inst Genet & Med, Naples, Italy

[2] Univ Naples Federico II, Dept Translat Med, Naples, Italy

[3] Univ Campania L Vanvitelli, Dept Biochem Biophys & Gen Pathol, Med Genet, Naples, Italy

[4] Texas Children Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX USA

[5] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[6] Univ Naples Federico II, Dept Biol, Naples, Italy

来源：

EMBO JOURNAL | 2020年 / 39卷 / 08期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

autophagy; Ezrin; miR-211; RPE; TFEB; PIGMENT EPITHELIUM; BINDING-SITE; ERM PROTEINS; IN-VIVO; AUTOPHAGY; RECEPTOR; TFEB; ACTIVATION; PHENOTYPE; MEMBRANE;

D O I：

10.15252/embj.2019102468

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：21