TBK1 kinase acts like a parking brake to prevent premature activation of NLRP3 inflammasome

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Activation of the NLRP3 inflammasome can be beneficial during infection and vaccination. Nonetheless, when NLRP3 activity is uncontrolled and chronic, it becomes detrimental and contributes to inflammation-driven pathology in diseases such as Alzheimer's disease, Parkinson's disease and atherosclerosis. In healthy individuals therefore, there must exist a licencing mechanism that prevents unwanted NLRP3 inflammasome responses. Here, we characterized one such mechanism. Using pharmacological and genetic approaches we showed that TBK1 limits the responses downstream of the NLRP3 inflammasome activation and it works against the PP2A phosphatase ON switch to balance the NLRP3 activity. Several viruses such as coronavirus SARS-CoV-2 are known to inhibit TBK1 activity as a part of their immune evasion strategy. We propose that TBK1 kinase acts like a parking brake that limits NLRP3 pathway activity, and that viruses that inhibit TBK1 boost the NLRP3-driven inflammation by removing an important break from this pathway. We now propose to characterise the mechanism behind our findings and its relevance to the current pandemic coronavirus disease.The team leading the proposal is made of PI (Jelena Bezbradica Mirkovic who is expert in macrophage biology, innate signaling and inflammasomes), highly productive inflammasome expert postdoc (Dr Benjamin Demarco) who will join the team in May 2021; the proteomics collaborators at Oxford (Prof Benedikt Kessler and Dr Roman Fischer), and the world-leader imaging expert collaborator at Kennedy (Prof Michael Dustin). Critically, preliminary data upon which this application is predicated are currently in revision for publication.