Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral 
properties, but less is known about how they induce cell death. Here, we show 
that both type I (α/β) and type II (γ) IFNs induce precipitous 
receptor-interacting protein (RIP)1/RIP3 kinase-mediated necrosis when the 
adaptor protein Fas-associated death domain (FADD) is lost or disabled by 
phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced 
necrosis proceeds via progressive assembly of a RIP1-RIP3 "necrosome" complex 
that requires Jak1/STAT1-dependent transcription, but does not need the kinase 
activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive 
protein kinase PKR, which then interacts with RIP1 to initiate necrosome 
formation and trigger necrosis. Although IFNs are powerful activators of 
necrosis when FADD is absent, these cytokines are likely not the dominant 
inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We 
also identify phosphorylation on serine 191 as a mechanism that disables FADD 
and collaborates with caspase inactivation to allow IFN-activated necrosis. 
Collectively, these findings outline a mechanism of IFN-induced RIP 
kinase-dependent necrotic cell death and identify FADD and caspases as negative 
regulators of this process.