Controlled detonation: evolution of necroptosis in pathogen defense

Necroptosis is a lytic form of programmed cell death that involves the swelling and rupture of dying cells. Although several necroptosis-inducing stimuli have been defined, in most cells this pathway is kept in check by the action of the pro-apoptotic protease caspase-8 and the IAP ubiquitin ligases. How and when necroptosis is triggered under physiological conditions therefore remains a persistent question. Because necroptosis likely arose as a defensive mechanism against viral infection, exploration of this question requires a consideration of host-pathogen interactions, and how the sensing of infection could sensitize cells to necroptosis. Here, we will discuss the role of necroptosis in the response to viral infection, consider why the necroptotic pathway has been favored during evolution, and describe emerging evidence for death-independent functions of key necroptotic signaling components.