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.

Automated summary

In the past decade, the importance of the necroptosis programmed cell death pathway in the pathophysiology of various diseases has been confirmed. The receptor interacting protein kinase (RIPK)1 and RIPK3, and the pseudokinase executioner protein, mixed lineage kinase domain-like (MLKL), have emerged as core components of the pathway. These proteins also serve as integrators of signals and add complexity to pathway regulation. This article describes the emerging concept of the protein network that tunes necroptotic signal transduction and how these events have diverged across species, possibly due to selective pressures from pathogens on the RIPK3-MLKL protein pair.