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通过AMPK对FNIP1的酸化诱导 lysosomal和线粒体生物发生
Nazma Malik1, Bibiana I Ferreira1, Pablo E Hollstein1
1Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
线粒体损伤激活了腺单酸激活蛋白激酶 (AMPK),该蛋白激活素相互作用蛋白1 (FNIP1). 这触发了TFEB核转移,启动了溶酶体和线粒体生物发生.
科学领域:
- 细胞代谢
- 线粒体功能
- 分子信号
背景情况:
- 细胞激活腺单激活蛋白激酶 (AMPK) 作为对线粒体毒素的反应.
- AMPK通过酸化和转录调节影响细胞代谢.
- 转录因子EB (TFEB) 在能量压力期间调解AMPK对溶酶基因表达的影响,但激活机制尚不清楚.
研究的目的:
- 阐明AMPK在响应线粒体应激时激活TFEB的机制.
- 确定参与TFEB激活的AMPK的直接分子点.
主要方法:
- 研究了AMPK,毛囊素相互作用蛋白1 (FNIP1) 和TFEB之间的相互作用.
- 使用酸化位点分析来确定AMPK的直接标.
- 评估了FNIP1化对TFEB核转移和下游基因表达的影响.
主要成果:
- 在FNIP1上,AMPK直接化五种血清残留物,抑制毛囊素 (FLCN) -FNIP1复合物.
- 通过AMPK化FNIP1对于TFEB转移到细胞核至关重要.
- 这一过程导致过氧体增殖器激活受体马协活性剂1-α (PGC1α) 和与雌激素相关的受体α (ERRα) 传递 RNA 的表达增加.
结论:
- 线粒体损伤启动了一个信号级联,涉及AMPK介导的FNIP1酸化.
- 这种信号通道对于TFEB的核进口至关重要.
- 这些发现揭示了因应细胞能量应激而导致 lysosomal 和线粒体生物发生的序列诱导机制.
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