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一个非正规的AKT1-TERT通路协调自和ERphagy
bioRxiv : the preprint server for biology
|December 12, 2025
概括
AKT1激酶通过酸化TERT,促进核转位和激活PERK,通过一种新的途径激活自. 这个保存轴恢复了蛋白质静止,并为ER质量控制受损的疾病提供了治疗策略.
科学领域:
- 细胞生物学 细胞生物学
- 自的分子机制 自的分子机制
- 神经科学是一个神经科学.
背景情况:
- 蛋白激酶通常抑制自,但在细胞应激期间激活自的机制尚未完全理解.
- 在自调节中,AKT激酶的作用是复杂的,正规途径表明抑制.
研究的目的:
- 阐明AKT1激酶激活自的非正规途径.
- 确定关键的分子参与者和转录机制参与压力诱导的自.
- 探索针对 Endoplasmic reticulum 质量控制有缺陷的疾病的这种途径的治疗潜力.
主要方法:
- 使用哺乳动物细胞系和遗传模型研究了AKT1激酶活性及其下游标.
- 利用蛋白组学和生物化学分析来确定酸化位点和蛋白质相互作用.
- 使用CRISPR/Cas9基因编辑和小分子抑制剂来剖析AKT1-TERT信号轴.
- 在保存模型生物 (C. elegans) 和人类诱导的多能干细胞 (iPSC) 中验证的发现.
主要成果:
- AKT1激酶通过一种非正规的途径促进自,其中包括在Serine 824中对端粒酶逆转录酶 (TERT) 的酸化.
- 化TERT转移到核中,与FOXO3和c-MYC形成一个转录复合体,以激活PERK.
- 这种PERK-ATF4信号级联放大了自基因表达,并通过TEX264和CCPG1.4诱导选择性的ER-phagy.
- AKT1-TERT-c-MYC-FOXO3轴在进化过程中得到保存,并且对于转基因后细胞的蛋白质稳定至关重要.
结论:
- 发现了一种新的转录机制,将AKT1激活与自开始和ER-phagy联系起来.
- 证明了AKT1-TERT-c-MYC-FOXO3轴在维持跨物种蛋白质稳定中的重要作用.
- 开发了一种一流的全性AKT2抑制剂,可以选择性地激活补偿性AKT1,恢复患病细胞的自,并提供治疗策略.
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