Functions of caspase 8: The identified and the mysterious

•Caspase-8 is required for death receptor apoptosis and, paradoxically, survival of some cell types.•This switch requires protein kinases of the RIP family, which engage a pathway known as necroptosis.•The pro-apoptotic and pro-survival functions of caspase-8 are regulated by the pseudo-caspase cFLIP.•The mechanism of how caspase-8 and cFLIP coordinate the switch between apoptosis and survival is unknown.•The reason why an apoptotic initiator has been co-opted as a critical survival factor is unknown.

Initially discovered as an initiator protease in apoptosis mediated by death receptors, caspase-8 is now known to have an apparently confounding opposing effect in securing cell survival. It is required to allow mouse embryo survival, and the survival of hematopoietic cells during their development and activation. Classic models in which caspase-8 is depleted or inhibited frequently result in inhibition of apoptosis, and conversion to death through a necrotic pathway. This bewildering switch is now known to be driven by activation of a pathway dependent on protein kinases of the RIP family, which engage a pathway known as necroptosis. If caspase-8 does not control this pathway, necrotic death results. The pro-apoptotic and pro-survival functions of caspase-8 are regulated by a specific interaction with the pseudo-caspase cFLIP, and it is thought that the heterocomplex between these two partners alters the substrate specificity of caspase-8 in favor of inactivating components of the RIP kinase pathway. The description of how caspase-8 and cFLIP coordinate the switch between apoptosis and survival is just beginning. The mechanism is not known, the differential targets are not known, and the reason of why an apoptotic initiator has been co-opted as a critical survival factor is only guessed at. Elucidating these unknowns will be important in understanding mechanisms and possible therapeutic targets in autoimmune, inflammatory, and metastatic diseases.