GATOR2复合体通过抑制MiT/TFEs的蛋白质降解来维持 lysosomal-autophagic 功能
Shu Yang1, Chun-Yuan Ting1, Mary A Lilly1
1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Molecular cell
|February 7, 2024
概括
该GATOR2复合体保护关键蛋白质 (MiT/TFEs) 免受降解,保持 lysosome 的功能. 这一发现揭示了GATOR2的存在.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 代谢调节 代谢调节 代谢调节
背景情况:
- 溶解体对于细胞代谢平衡至关重要.
- 微的bHLH-LZ转录因子 (MiT/TFEs) 调节了溶酶体和自基因.
- 在各种癌症中,MiT/TFEs经常存在失调.
研究的目的:
- 研究GATOR2复合体在维持 lysosomal 功能中的作用.
- 确定 GATOR2 影响 MiT/TFE 的机制.
- 探索GATOR2在MiT/TFE驱动癌症中的相关性.
主要方法:
- 使用GATOR2淘汰HeLa细胞来研究MiT/TFE降解.
- 通过E3结合酶对MiT/TFEs的研究无处不在.
- 分析了GATOR2在癌症细胞系中的保护作用 (胰腺管道腺癌,Xp11转位细胞癌).
主要成果:
- GATOR2 独立于 TORC1.1,可以保护 MiT/TFEs 免受蛋白质体降解.
- 失去GATOR2导致MiT/TFE无处不在和降解,导致溶酶体功能障碍.
- 在由MiT/TFE过度激活驱动的癌症中,GATOR2保护了MiT/TFE蛋白.
结论:
- 在调节TORC1.1.方面,GATOR2复合体起着独立的作用.
- GATOR2对于保护MiT/TFE蛋白质免受降解至关重要.
- GATOR2是协调细胞新陈代谢和 lysosomal-autophagic系统的核心.
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