The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by <i>Yersinia</i>
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
Abstract
Cell death limits pathogens During infection, Yersinia inhibition of the protein kinase TAK1 triggers cleavage of the pore-forming protein gasdermin D (GSDMD), which leads to a kind of inflammatory cell death called pyroptosis. In a genome-wide screen, Zheng et al. identified a lysosome-tethered regulatory supercomplex as being a critical driver of Yersinia -induced pyroptosis. The activity of the GTPase Rag and lysosomal tethering of Rag-Ragulator were required to recruit and activate the kinase RIPK1 and protease caspase-8 to cleave GSDMD, which causes cell death and limits infection. By contrast, Rag-Ragulator was not required for inflammasome-mediated pyroptosis. Thus, metabolic signaling on lysosomes can regulate cell death during pathogenic bacterial infection. Science , abg0269, this issue p. eabg0269