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).