Whole-genome CRISPR screen identifies regulators of RIPK1-mediated inflammatory cell death, PANoptosis

Transforming growth factor-beta-activated kinase 1 (TAK1) is a central regulator of innate immunity, cell death, inflammation and cellular homeostasis. Therefore, many pathogens carry TAK1 inhibitors (TAK1i). To counteract this for host defense, inhibition or deletion of TAK1 induces spontaneous inflammatory cell death, PANoptosis, through the RIPK1-PANoptosome complex, containing the NLRP3 inflammasome and caspase-8/FADD/RIPK3 as integral components; however, PANoptosis can also promote pathological inflammation. Therefore, understanding molecular mechanisms that regulate TAK1i-induced cell death is essential. Here, we report a genome-wide CRISPR screen in macrophages that identified TAK1i-induced PANoptosis regulators.