Synergy Between TNFα and Proteostatic Stress Drives Cell Death and Guard Immunity

The production and sensing of type I interferons (IFN-I) are critical for antiviral defense, yet most virus-infected cells do not produce IFN-I or upregulate IFN-stimulated genes. Using quantitative proteomics and global protein synthesis measurements, we show that productive viral infection globally down-regulates protein synthesis, restricting the IFN response. Guard immunity, which responds to disruptions in essential cellular processes, might compensate for the lack of IFN-I response by rapidly killing infected cells. However, non-pathological stressors can also disrupt proteostasis, making it unclear how cells decide to trigger guard immunity. We hypothesized that TNF, produced by macrophages, provides a contextual signal allowing specificity. Using live-cell fluorescence microscopy and mathematical modeling, we showed that TNF synergizes with the rapid decay of the anti-apoptotic protein c-FLIP to induce cell death and prevent viral spread. Our findings demonstrate that TNF contextualizes proteostasis loss as non-sterile, enabling the activation of guard immunity to counteract viral infection.