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bioRxiv · 10.1101/2024.06.12.598679

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

Sonnett, M.·Centofanti, E.·Boersma, S.·Brambach, M.·Peshkin, L.·Tatavosian, R.·Oyler-Yaniv, A.·Oyler-Yaniv, J.
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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 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.

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Sonnett, M., Centofanti, E., Boersma, S., Brambach, M., Peshkin, L., Tatavosian, R., Oyler-Yaniv, A., Oyler-Yaniv, J.. 2024-06-14. Synergy Between TNFα and Proteostatic Stress Drives Cell Death and Guard Immunity. https://doi.org/10.1101/2024.06.12.598679

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