中国科学院上海巴斯德研究所刘星、美国哈佛医学院Judy Lieberman等研究人员合作发现，溶酶体Rag-Ragulator复合物调控RIPK1和caspase-8介导的细胞焦亡。该研究于2021年6月25日发表于国际一流学术期刊《科学》。
研究人员表示，宿主细胞启动细胞死亡程序来限制病原体感染。巨噬细胞中致病性耶尔森菌对转化生长因子-β-活化激酶1（TAK1）的抑制能够触发受体相互作用的丝氨酸-苏氨酸蛋白激酶1（RIPK1）-依赖的caspase-8切割gasdermin D（GSDMD）和炎症细胞死亡（细胞焦亡）。
通过caspase-8依赖性细胞焦亡介导因子的全基因组CRISPR筛选，研究人员确定了溶酶体卵泡素（FLCN）-卵泡素相互作用蛋白2（FNIP2）-Rag-Ragulator超级复合物的意外作用，该复合物可调节代谢信号和哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）。
为了响应耶尔森氏菌感染，Fas相关死亡域（FADD）、RIPK1和caspase-8被招募到 Rag-Ragulator，导致RIPK1磷酸化和caspase-8激活。焦亡激活取决于Rag鸟苷三磷酸酶活性和Rag-Ragulator的溶酶体束缚，而不是mTORC1。因此，溶酶体代谢调节因子Rag-Ragulator指导对耶尔森菌的炎症反应。
附：英文原文
Title: The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia
Author: 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
Issue&Volume: 2021/06/25
Abstract: 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 CRISPR screen to uncover mediators of caspase-8–dependent pyroptosis identified an unexpected role of the lysosomal folliculin (FLCN)–folliculin-interacting protein 2 (FNIP2)–Rag-Ragulator supercomplex, which regulates metabolic signaling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, Fas-associated death domain (FADD), RIPK1, and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag guanosine triphosphatase activity and lysosomal tethering of Rag-Ragulator but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.
DOI: 10.1126/science.abg0269
Source: https://science.sciencemag.org/content/372/6549/eabg0269