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

ABSTRACT: 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 TNFα, produced by macrophages, provides a contextual signal allowing specificity. Using live-cell fluorescence microscopy and mathematical modeling, we showed that TNFα synergizes with the decay of the anti-apoptotic protein c-FLIP to induce cell death and prevent viral spread. Our findings demonstrate that TNFα contextualizes the loss of proteostasis as non-sterile, enabling the activation of guard immunity to counteract viral infection.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

DISEASE(S): Herpes Simplex

SUBMITTER: Matthew Sonnett  

LAB HEAD: Jennifer Oyler-Yaniv

PROVIDER: PXD053765 | Pride | 2026-10-05

REPOSITORIES: Pride