上睑下垂
裂谷1
坏死性下垂
细胞生物学
炎症体
生物
程序性细胞死亡
时尚
耶尔森尼亚
磷酸化
激酶
半胱氨酸蛋白酶
mTORC1型
细胞凋亡
化学
蛋白激酶B
生物化学
受体
遗传学
细菌
作者
Zengzhang Zheng,Wanyan Deng,Yang Bai,Rui Miao,Shenglin Mei,Zhibin Zhang,Youdong Pan,Yi Wang,Rui Min,Fan Deng,Zeyu Wu,Wu Li,Pengcheng Chen,Tianchi Ma,Xiwen Lou,Judy Lieberman,Xing Liu
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2021-06-25
卷期号:372 (6549)
被引量:110
标识
DOI:10.1126/science.abg0269
摘要
Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor-β-activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen to uncover mediators of caspase-8-dependent pyroptosis identified an unexpected role of the lysosomal FLCN-FNIP2-Rag-Ragulator supercomplex, which regulates metabolic signalling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, FADD, RIPK1 and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag GTPase activity and lysosomal tethering of Rag-Ragulator, but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.
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