色素性视网膜炎
自噬
吞噬作用
视网膜色素上皮
人类视网膜的基因治疗
细胞生物学
RPE65型
颜料
视网膜
化学
生物
生物化学
细胞凋亡
有机化学
作者
Yi Zhen,Chaojuan Wen,Han Du,Yingwei Wang,Sheng Chen,Jie Liu,Shuhan Zhang,Junwen Wang,Xueshan Xiao,Shiqiang Li,Xiaoyun Jia,Yi Jiang,Jiamin Ouyang,Panfeng Wang,J. Fielding Hejtmancik,Wenmin Sun,Huangxuan Shen,Qingjiong Zhang
标识
DOI:10.1002/advs.202512305
摘要
Autophagy is pivotal for cellular homeostasis and photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) in retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa (RP). Yet, the mechanism of autophagy in the RPE remains largely unknown. RP is an inherited retinal degenerative condition, whose candidate genes provide avenues for dissecting novel autophagy factors. Here, whole exome sequencing of RP patients identified biallelic variants in TRIM49, a primate-specific gene involved in autophagy, as a novel cause of RP. Among human tissues TRIM49 is highly expressed in the RPE. In human RPE cells, deficiency of TRIM49 significantly disturbs cellular homeostasis and impairs the POS phagocytosis. Importantly, suppressed basal autophagy flux is present in TRIM49-depleted RPE cells, whereas enhanced autophagy flux is present in RPE cells overexpressing TRIM49. Variations of TRIM49 after treatment with multiple autophagy modulators indicate that TRIM49 is involved in the initiation of autophagy. TRIM49 interacts with the key regulator of autophagy initiation ULK1. Deficiency of TRIM49 down-regulates and overexpression of TRIM49 up-regulates ULK1 expression. Altogether, these findings identify TRIM49 as a critical regulator of ULK1-mediated autophagy and POS phagocytosis by the RPE, suggesting that RPE autophagy is a potential therapeutic target for retinal degenerative diseases.
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