TBK1 and IKKe 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 IKKe act like brakes on cell death pathways. Jelena explained: ‘In macrophages, TBK1 and IKKe act as a brake that prevents premature activation of RIPK1, and another key death-inducing pathway, the NLRP3 inflammasome.
When TBK1 is missing, the recycling system within cells, specifically the endosomal vesicles, becomes disorganised. This disruption signals the cell stress, lowering the threshold for NLRP3 activation and leading to uncontrolled cell death.’
The immune response and cellular processes responding to loss or mutation of TBK1 and IKKe on the RIPK1 and NLRP3 pathways.
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 IKKe 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.