RIPK3 in cell death and inflammation: the good, the bad, and the ugly

Necroptosis is a form of cell death that can be observed downstream of death receptor or pattern recognition receptor signaling under certain cellular contexts, or in response to some viral and bacterial infections. The receptor interacting protein kinases-1 (RIPK1) and RIPK3 are at the core of necroptotic signaling, among other proteins. Because this pathway is normally halted by the pro-apoptotic protease caspase-8 and the IAP ubiquitin ligases, how and when necroptosis is triggered in physiological settings are ongoing questions. Interestingly, accumulating evidence suggests that RIPK3 has functions beyond the induction of necroptotic cell death, especially in the areas of tissue injury and sterile inflammation. Here, we will discuss the role of RIPK3 in a variety of physiological conditions, including necroptotic and non-necroptotic cell death, in the context of viral and bacterial infections, tissue damage, and inflammation.