TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways

Authors: Fabian A. Fischer, Benjamin Demarco, Felicia Chan Hui Min, Hui Wen Yeap, Dominic De Nardo, Kaiwen W. Chen, Jelena S. Bezbradica

Published: 2025-03-07

DOI: 10.1126/sciadv.adq1047

Source: Full article


Abstract

The loss of TBK1, or both TBK1 and the related kinase IKKε, results in uncontrolled cell death–driven inflammation. Here, we show that the pathway leading to cell death depends on the nature of the activating signal. Previous models suggest that in steady state, TBK1/IKKε-deficient cells die slowly and spontaneously predominantly by uncontrolled tumor necrosis factor–RIPK1–driven death. However, upon infection of cells that express the NLRP3 inflammasome, (e.g., macrophages), with pathogens that activate this pathway (e.g.,