The FLIP Side of Life

The anti-apoptotic protein c-FLIP, a catalytically inactive homolog of caspase-8, is an important regulator of death receptor signaling. Death receptors constitute a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas, DR4, and DR5. When activated by their respective ligands, TNF, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL), these receptors cause caspase-8-mediated apoptosis. If caspase-8 activity is blocked, however, then these receptors promote death by necroptosis (programmed necrosis), which requires the kinases receptor-interacting kinase 1 (RIPK1) and RIPK3, as well as mixed-lineage kinase-like protein. Necroptosis has become the subject of intense research because it promotes inflammation, and inhibiting this pathway can limit extensive tissue damage and even lethality in inflammatory syndromes. A study now reports on the role of c-FLIP in vivo from experiments with a range of conditional knockout mice and demonstrates that c-FLIP plays a critical role in inhibiting both apoptotic and necroptotic cell death within the whole mouse.