FIG. 1.

Schematic of interferon (IFN)-γ-activated pronecrotic and prosurvival signaling pathways. IFN-γ utilizes classical Jak/STAT signaling downstream of the IFN-γ receptor (IFNGR) to induce expression of pronecrotic genes (such as those encoding RIP1, PKR, and MLKL proteins) and activate R1P1/RIP3 kinase-dependent necrosis. The IFN-γ-induced necrotic pathway is held in check by the adaptor protein FADD, and can be inhibited by the RIP1 kinase blocker Necrostatin-1. In parallel, IFN-γ also activates NF-κB via canonical IκB kinases (IKK)-β-dependent signaling to induce expression of prosurvival genes such as sod2. As NF-κB target genes protect against IFN-γ-activated necrosis, disabling NF-κB signaling (by bortezomib, for example) sensitizes cells to IFN-γ-induced necrotic death that proceeds via accumulation of mitochondrial reactive oxygen species (ROS).