mTORC1型
生物
细胞生物学
衰老
下调和上调
RNA结合蛋白
自噬
雷帕霉素的作用靶点
信号转导衔接蛋白
基因敲除
内皮功能障碍
PI3K/AKT/mTOR通路
信号转导
信使核糖核酸
内分泌学
细胞培养
基因
生物化学
细胞凋亡
遗传学
作者
Fanglin Niu,Zhuozhuo Li,Yuanyuan Ren,Zi Li,Hua Guan,Yang Li,Yan Zhang,Yirong Li,Jun Yang,Qian Lü,Wenzhen Shi,Xiaobin Fan,Jinli Li,Lele Shi,Yi Yu,Yuyan Xiong
出处
期刊:Redox biology
[Elsevier]
日期:2023-09-01
卷期号:65: 102824-102824
标识
DOI:10.1016/j.redox.2023.102824
摘要
Vascular endothelial cells (ECs) senescence plays a crucial role in vascular aging that promotes the initiation and progression of cardiovascular disease. The mutation of Grb10-interacting GYF protein 2 (GIGYF2) is strongly associated with the pathogenesis of aging-related diseases, whereas its role in regulating ECs senescence and dysfunction still remains elusive. In this study, we found aberrant hyperexpression of GIGYF2 in senescent human ECs and aortas of old mice. Silencing GIGYF2 in senescent ECs suppressed eNOS-uncoupling, senescence, and endothelial dysfunction. Conversely, in nonsenescent cells, overexpressing GIGYF2 promoted eNOS-uncoupling, cellular senescence, endothelial dysfunction, and activation of the mTORC1-SK61 pathway, which were ablated by rapamycin or antioxidant N-Acetyl-l-cysteine (NAC). Transcriptome analysis revealed that staufen double-stranded RNA binding protein 1 (STAU1) is remarkably downregulated in the GIGYF2-depleted ECs. STAU1 depletion significantly attenuated GIGYF2-induced cellular senescence, dysfunction, and inflammation in young ECs. Furthermore, we disclosed that GIGYF2 acting as an RNA binding protein (RBP) enhances STAU1 mRNA stability, and that the intron region of the late endosomal/lysosomal adaptor MAPK and mTOR activator 4 (LAMTOR4) could bind to STAU1 protein to upregulate LAMTOR4 expression. Immunofluorescence staining showed that GIGYF2 overexpression promoted the translocation of mTORC1 to lysosome. In the mice model, GIGYF2flox/flox Cdh-Cre+ mice protected aged mice from aging-associated vascular endothelium-dependent relaxation and arterial stiffness. Our work discloses that GIGYF2 serving as an RBP enhances the mRNA stability of STAU1 that upregulates LAMTOR4 expression through binding with its intron region, which activates the mTORC1-S6K1 signaling via recruitment of mTORC1 to the lysosomal membrane, ultimately leading to ECs senescence, dysfunction, and vascular aging. Disrupting the GIGYF2-STAU1-mTORC1 signaling cascade may represent a promising therapeutic approach against vascular aging and aging-related cardiovascular diseases.
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