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通过新的胆固醇合成,ATR促进mTORC1的活动

Naveen Kumar Tangudu^1,2, Alexandra N Grumet³, Richard Fang^1,2

¹Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

bioRxiv : the preprint server for biology

|November 14, 2023

概括

ATAXIA Telangiectasia和Rad3相关蛋白 (ATR) 通过通过胆固醇合成激活机械性目标拉巴胺复合物1 (mTORC1) 来增强细胞代谢. 这条通路对于细胞功能至关重要,即使在正常条件下.

科学领域:

细胞生物学细胞生物学
分子生物学分子生物学
生物化学生物化学

背景情况:

通过反机制,DNA损伤和细胞代谢密切相关.
抗衰退 (Telangiectasia) 和与Rad3相关的蛋白质 (ATR) 和机械性目标拉巴胺复合物1 (mTORC1) 分别是DNA损伤反应和新陈代谢的关键调节者.
众所周知,ATR在复制压力期间调节mTORC1,但激活机制尚不清楚,特别是在未被扰乱的细胞中.

研究的目的:

研究ATR在基底条件下调节mTORC1活动中的作用.
阐明链接ATR和mTORC1信号的分子机制.
探索ATR,mTORC1和胆固醇代谢之间的联系.

主要方法:

利用各种细胞模型研究ATR和mTORC1信号.
研究了兰醇合成酶 (LSS) 在ATR介导的mTORC1激活中的作用.
在ATR抑制后通过补充兰醇或胆固醇进行了救援实验.
评估了mTOR定位到 lysosome 的情况.

主要成果:

在基底条件下,ATR在各种细胞类型中促进mTORC1活动.
在ATR上调的lanosterol合成酶 (LSS),驱动 de novo胆固醇合成和mTORC1激活,独立于CHK1和TSC复合体.
失去p16会增强ATR活动和mTORC1信号传递.
补充兰醇或胆固醇可以挽救ATR抑制引起的mTORC1活动抑制,促进mTOR lysosomal定位.

结论:

通过调节胆固醇代谢,ATR信号与mTORC1激活有关.
由ATR诱导的胆固醇合成是一种用于mTORC1激活的新机制.
这种ATR-胆固醇-mTORC1轴即使在未被扰乱的细胞中也很活跃,在p16缺乏的环境中尤其重要.

关键词:

这是一个ATRATRATRATR.胆固醇胆固醇胆固醇是一种兰醇合成酶的使用 lysosome 溶解酶体是如何形成的在 mTORC1 的情况下,mTORC1 是 mTORC1.代谢代谢代谢代谢 p16 p16 在这个问题上.

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