m6A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis
m6A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis
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DOI：
10.1016/j.celrep.2022.111671
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发表时间：
2022-11-15
期刊：
影响因子：
8.8
通讯作者：
Liu, Qing-Huai
中科院分区：
文献类型：
--
作者：
Chen, Xue;Wang, Ying;Liu, Qing-Huai
视网膜相关性黄斑变性（AMD）是导致老年人不可逆视力丧失的主要原因，其发病机制尚不清楚。在此，我们检测AMD患者视网膜色素上皮（RPE）中下调的circSPECC 1表达。在RPE细胞中，circSPECC 1不足导致氧化应激诱导的铁凋亡、去极化和不规则的脂质代谢。一致地，在小鼠中，circSPECC 1缺陷诱导视觉障碍和RPE异常并中断视网膜稳态。在机械上，circSPECC 1转录物的核输出取决于其N6-甲基腺苷（m6 A）水平，YTHDC 1作为读取器。CircSPECC 1直接吸收miR-145- 5 p以阻断其与CDKN 1A的相互作用。过表达miR-145- 5 p会加剧RPE功能障碍，模拟circSPECC 1沉默效应。由circSPECC 1不足诱导的视网膜表型通过miR-145- 5 p抑制而减轻，并且通过miR-145- 5 p过表达而加重。总体而言，circSPECC 1通过m6 A修饰和海绵状miR-145- 5 p介导，抵抗氧化应激损伤并维持RPE中的脂质代谢。circSPECC 1的药理学补充是萎缩性视网膜病如AMD的有希望的治疗选择。
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population with unclear pathogenic mechanism. Herein, we detect downregulated circSPECC1 expression in retinal pigment epithelium (RPE) of AMD patients. In RPE cells, circSPECC1 insufficiency leads to oxidative stress-induced ferroptosis, depolarization, and irregular lipid metabolism. Consistently, in mice, circSPECC1 deficiency induces visual impairments and RPE anomalies and interrupts retinal homeostasis. Mechanically, nuclear export of circSPECC1 transcript depends on its N6-methyladenosine (m6A) level with YTHDC1 as the reader. CircSPECC1 directly sponges miR-145-5p to block its interaction with CDKN1A. Overexpressing miR-145-5p aggravates RPE dysfunctions, mimicking circSPECC1 silencing effects. Retinal phenotypes induced by circSPECC1 insufficiency are alleviated by miR-145-5p inhibition and are aggravated by miR-145-5p overexpression. Collectively, circSPECC1, mediated by m6A modification and sponging miR-145-5p, resists oxidative stress injuries and maintains lipid metabolism in RPE. Pharmacological supplementation of circSPECC1 is a promising therapeutic option for atrophic retinopathies like AMD.