通过UBE2F-SAG轴的RHEB脱增强了mTORC1的活动,并加剧了肝脏瘤发生
Fengwu Zhang1,2,3, Xiufang Xiong1,2,3, Zhijian Li1,2,3
1Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
The EMBO journal
|January 6, 2025
概括
研究人员发现,UBE2F的缩向RHEB,影响mTORC1的信号传递. 这一发现揭示了UBE2F-SAG作为脂肪肝和肝细胞癌等肝脏疾病的潜在治疗点.
科学领域:
- 分子生物学分子生物学
- 细胞信号传输 细胞信号传输
- 生物化学 生物化学
背景情况:
- 小型GTPase RHEB激活了mTORC1.1. 这样一来.
- 化改变了蛋白质的活性,局部化和稳定性.
- 在RHEB调节中,缩的作用以前是未知的.
研究的目的:
- 为了调查RHEB是否是一种化基质.
- 阐明尼迪化如何影响RHEB功能的机制.
- 探索UBE2F介导的RHEB缩在肝脏疾病中的作用.
主要方法:
- 细胞培养实验以评估mTORC1活动和RHEB缩.
- 耗尽UBE2F并研究其对细胞周期,生长和自的影响.
- 分析RHEB脱位 (K169) 以及其对溶酶体局部化和GTP结合的影响.
- 生产肝脏特异性的Ube2f淘汰赛小鼠,以研究肥胖症和瘤发生.
- 对UBE2F表达,mTORC1活性和肝细胞癌患者存活率的相关性分析.
主要成果:
- RHEB被确定为NEDD8结合E2酶UBE2F的基质.
- UBE2F的枯竭使mTORC1失活,抑制细胞增殖并诱导自.
- 与E3结合酶SAG一起的UBE2F在K169处对RHEB进行脱,增强了溶酶体局部化和GTP结合.
- 在Pten-loss模型中,肝脏特异性的Ube2f淘汰会降低脂肪和瘤发生.
- 在肝细胞癌患者中,UBE2F表达和mTORC1活性与生存相关.
结论:
- 该UBE2F-SAG轴对RHEB进行无,调节其功能和mTORC1信号.
- UBE2F在肝脏瘤发生和非酒精性脂肪肝疾病中发挥着关键作用.
- UBE2F-SAG轴代表了肝脏病理的一个有前途的治疗标.
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