by University of Oxford

Loss of TBK1/IKKε disrupts the endosomal homeostasis and lowers the threshold for NLRP3 activation. Credit: Science Advances (2025). DOI: 10.1126/sciadv.adq1047

New research from the Kennedy Institute has revealed how two important proteins, TBK1 and IKKε, play a crucial role in preventing premature cell death, which can lead to serious inflammation in the body. The findings are particularly relevant for people with a mutation in the TBK1 gene who often develop multiorgan inflammation caused by excessive cell death even in the absence of any infection.

TBK1 and IKKε are two highly related kinases, which are enzymes that help regulate various cellular processes, including the control of anti-viral immune responses. While they are well-known for their role in fighting off viral infections, this new study, published in Science Advances, highlights their equally important function in controlling cell death.

When TBK1 is lost or mutated, it fails to perform its protective role, allowing two major cell death pathways, RIPK1 and NLRP3, to become overactive. This overactivity leads to excessive cell death and people with a mutation in the TBK1 gene often experience inflammation in multiple organs.

Led by Jelena Bezbradica, Associate Professor of Immunology at the Kennedy Institute, the study found that TBK1 and IKKε act like brakes on cell death pathways. Bezbradica explained, “In macrophages, TBK1 and IKKε act as a brake that prevents premature activation of RIPK1, and another key death-inducing pathway, the NLRP3 inflammasome.

Model of how TBK1/IKKε prevent cell death: by inhibiting premature activation of RIPK1 and NLRP3 in death-inducing pathways. Credit: Science Advances (2025). DOI: 10.1126/sciadv.adq1047

“When TBK1 is missing, the recycling system within cells, specifically the endosomal vesicles, becomes disorganized. This disruption signals the cell stress, lowering the threshold for NLRP3 activation and leading to uncontrolled cell death.”

The findings enhance our understanding of how certain genetic mutations can lead to chronic inflammation and organ damage. On the other hand, results imply that any pathogen-induced interference with normal TBK1 and IKKε function, e.g., as part of their anti-viral immune evasion strategy, may remove the brake from the death pathways, leading to the death and removal of the compromised cell, but this remains to be tested.

More information: Fabian A. Fischer et al, TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways, Science Advances (2025). DOI: 10.1126/sciadv.adq1047

Journal information:Science Advances

Provided by University of Oxford

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