Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling

Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain-like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds the necroptotic signaling core and that this network, rather than acting universally, tunes necroptosis in a context-, cell type-, and species-dependent manner. Such a high degree of mechanistic flexibility is likely an important property that helps necroptosis operate as a robust, emergency form of cell death.