Activation of death receptors can induce intrinsic cell death through formation of the 'necrosome' kinase complex composed of RIP1 and RIP3. However, this process is tightly regulated by FADD, caspase 8 and c-FLIP. In the Proceedings of the National Academy of Science, Thapa et al. describe an interferon-induced necroptosis pathway that is independent of signaling via death receptors. Both interferon-α/β and interferon-γ trigger upregulation of the double-stranded RNA–dependent protein kinase PKR, which interacts with RIP1 and is necessary for formation of the RIP1-RIP3 'necrosome'. Inhibition of either interferon signaling or PKR diminishes necroptosis. Notably, necroptosis occurs only when FADD is disabled by phosphorylation of Ser191, which occurs during the G2-M stage of the cell cycle. This induced death pathway might be a failsafe mode of innate immunity to control infection by viruses or bacteria that express apoptosis-inhibitor proteins.

Proc. Natl. Acad. Sci. USA (29 July 2013) doi:10.1073/pnas.1301218110