The web of death: the expanding complexity of necroptotic signaling.

The past decade has seen the emergence of the necroptosis programmed cell death pathway as an important contributor to the pathophysiology of myriad diseases. The receptor interacting protein kinase (RIPK)1 and RIPK3, and the pseudokinase executioner protein, mixed lineage kinase domain-like (MLKL), have grown to prominence as the core pathway components. Depending on cellular context, these proteins also serve as integrators of signals, such as post-translational modifications and protein or metabolite interactions, adding layers of complexity to pathway regulation. Here, we describe the emerging picture of the web of proteins that tune necroptotic signal transduction and how these events have diverged across species, presumably owing to selective pressures of pathogens upon the RIPK3–MLKL protein pair. Necroptosis is a lytic programmed cell death pathway initiated by death receptors and pathogen receptors, which is believed to have ancestrally evolved for host defense, but is frequently dysregulated in human disease. The core components of the pathway are the protein kinases, receptor interacting protein kinase (RIPK)1 and RIPK3, and the pseudokinase mixed lineage kinase domain-like (MLKL), which are responsible for membrane perturbation and cell death. The past decade has seen increasing complexity and implication of additional layers of regulation, through protein and metabolite interactions and post-translational modifications, to tune the activities and necroptotic functions of RIPK1, RIPK3, and MLKL. Many RIPK1, RIPK3, and MLKL modifications and interactions appear to be dependent on the cellular context, the necroptotic stimulus, and the species in question, which limits reductionist approaches to understanding the pathway. [ABSTRACT FROM AUTHOR]