对于MTORC1和TFEB的PIKFYVE依赖的调节
Junya Hasegawa1,2, Ken Inoki1,3,4, Lois S Weisman1,5
1Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
Autophagy reports
|May 21, 2025
概括
抑制PIKFYVE使转录因子EB (TFEB) 脱,并促进其核转位,激活自和溶酶体基因,即使在富含营养的条件下. 这通过破坏MTORC1相互作用而发生,允许PP2A酸酶活性.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 自和溶酶体生物学 自和溶酶体生物学
背景情况:
- 转录因子EB (TFEB) 调节自和溶酶体生物发生.
- 在营养丰富的条件下,TFEB活性被MTORC1酸化抑制,防止核转位.
- 营养素的可用性决定了TFEB通过MTORC1信号通路的活动.
研究的目的:
- 调查PIKFYVE在规范TFEB活动和核转移方面的作用.
- 阐明PIKFYVE抑制影响TFEB酸化和局部化的机制.
- 了解PIKFYVE如何与MTORC1-TFEB信号轴相互作用.
主要方法:
- 细胞测定以评估TFEB酸化和核转移.
- 药理上抑制PIKFYVE和MTORC1.1. 这两种药物.
- 分析TFEB,MTORC1和PP2A之间的蛋白质与蛋白质相互作用.
- 研究RRAG小GTPases在PIKFYVE介导调节中的作用.
主要成果:
- 抑制PIKFYVE会导致TFEB脱和核转移,而不依赖于营养状况.
- 这种效应取决于蛋白质酸酶2 (PPP2/PP2A) 的活性.
- 抑制PIKFYVE会破坏TFEB和MTORC1之间的相互作用,但不会破坏TFEB和PPP2.
- PIKFYVE通过RRAG GTPases调节MTORC1局部化到溶酶体和TFEB酸化.
结论:
- PIKFYVE通过促进MTORC1-依赖酸化来作为TFEB活性抑制剂.
- 抑制PIKFYVE将TFEB从MTORC1控制中释放出来,促进其转录程序.
- PIKFYVE在将 lysosomal营养感应与TFEB介导的基因表达相结合起着至关重要的作用.
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