Lysosomal Rag-Regulator Complex 许可 RIPK1 和Yersinia 的 Caspase-8 介导的灭
Zengzhang Zheng1,2, Wanyan Deng1,2, Yang Bai2,3
1The Joint Center for Infection and Immunity between Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center (Guangzhou, 510623, China) and Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
Science (New York, N.Y.)
|January 21, 2022
概括
致病性Yersinia感染会引发炎症性细胞死亡的一种形式. 研究人员发现 lysosomal Rag-Ragulator复合体意外地调解了这种反应,独立于mTORC1的信号传递.
科学领域:
- 细胞生物学
- 免疫学
- 微生物学
背景情况:
- 宿主细胞使用细胞死亡途径来对抗病原体的入侵.
- 致病的Yersinia抑制了巨细胞中的TAK1,从而通过caspase-8和GSDMD裂变导致了RIPK1依赖性热.
研究的目的:
- 在Yersinia感染期间识别卡斯帕-8依赖性热的新媒介.
- 阐明 lysosomal FLCN-FNIP2-Rag-Ragulator复合体在Yersinia诱导的炎症细胞死亡中的作用.
主要方法:
- 全基因组的CRISPR选用于识别调节热的基因.
- 共同免疫沉试验用于研究蛋白质复合体的形成.
- 对Rag-Ragulator的GTPase活性和溶酶局部化的分析.
主要成果:
- 一个CRISPR屏幕显示了 lysosomal FLCN-FNIP2-Rag-Ragulator超级复合体作为热的关键调节器.
- 在Yersinia感染时,FADD,RIPK1和caspase-8被招募到Rag-Ragulator复合体中.
- RIPK1的酸化和卡斯巴酶8的激活取决于Rag GTPase的活性和Rag-Ragulator的 lysosomal tethering,而不是mTORC1的信号传递.
结论:
- 溶酶体Rag-Ragulator复合体是Yersinia诱导的热的意想不到的媒介.
- 拉格调节器作为一个信号中心,指导对Yersinia感染的炎症反应.
- 这一发现揭示了溶酶体代谢信号与先天免疫反应之间的新联系.
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