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.
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Dempsey, L. Interferon-induced necroptosis. Nat Immunol 14, 892 (2013). https://doi.org/10.1038/ni.2700
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DOI: https://doi.org/10.1038/ni.2700