The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia

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