氨基酸在通过溶酶体定位增强mTOR激活中的协同作用
Oralia M Kolaczkowski1, Baley A Goodson1, Valeria Montenegro Vazquez1
1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, 87131, USA.
bioRxiv : the preprint server for biology
|October 17, 2024
概括
特定的氨基酸,特别是芳香的氨基酸,驱动 lysosome 向细胞外围定位,影响细胞功能. 这种运动与其他氨基酸相结合,协同增强了mTOR信号传递,特别是在癌细胞中.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 溶酶体的定位对细胞功能至关重要,并受到氨基酸等营养素的影响.
- 外围溶解体与癌细胞运动和生长有关,但精确的氨基酸调节仍不清楚.
研究的目的:
- 研究单个氨基酸如何影响 lysosome 定位及其潜在的分子机制.
- 探索氨基酸调节的溶酶体定位和mTOR等代谢信号通路之间的相互作用.
- 评估这些发现在乳腺癌细胞中的相关性.
主要方法:
- 开发一种高含量成像系统,用于对溶酶体分布进行定量分析.
- 对15种常见的细胞培养氨基酸进行选,以检测它们对溶酶体定位的影响.
- 研究涉及氨基酸诱导的溶酶体运输的分子途径.
- 评估mTOR激活反应的组合氨基酸治疗.
- 在正常与癌症乳腺细胞中对 lysosome 定位和癌细胞行为进行比较分析.
主要成果:
- 在15种测试的氨基酸中,有10种促进了溶酶体向细胞外围的再分配,芳香氨基酸显示出最显著的效果.
- 这种重新分配是由SLC38A9-BORC-kinesin 1/3轴对外传输和Rab7/JIP4对内传输的抑制介导的.
- 芳香氨基酸,如单独的氨酸,并没有激活mTOR,但与氨酸协同增强mTOR活性,这种协同取决于外围 lysosome 定位.
- 与非癌细胞相比,乳腺癌细胞对 fenilalanine 诱导的溶酶体分散的敏感性增加.
- 抑制氨基酸载体LAT1降低了外围溶解体,并损害了癌细胞迁移和增殖.
结论:
- lysosome 定位和 mTOR 信号由不同的氨基酸组调节.
- 通过结合 lysosome-dispersing 和 mTOR-activating 氨基酸来协同增强 mTOR 活性,这取决于 lysosome 外围化.
- 氨基酸调节的溶酶体定位在癌细胞迁移和增殖中起着重要作用,呈现出潜在的治疗点.
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