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

在感染和疫苗接种期间，激活NLRP3炎症体是有益的。然而，当NLRP3的活动不受控制和慢性时，它就会变得有害，并在阿尔茨海默病、帕金森病和动脉粥样硬化等疾病中促成炎症驱动的病理。因此，在健康的个体中，必须存在一种许可机制来防止不必要的NLRP3炎症体反应。在这里，我们描述了一种这样的机制。利用药理学和遗传学方法，我们证明了TBK1限制了NLRP3炎症体激活下游的反应，并与开关上的PP2A磷酸酶一起工作，以平衡NLRP3的活性。已知有几种病毒，如冠状病毒SARS-CoV-2，作为其免疫逃避策略的一部分，可以抑制TBK1的活性。我们认为，TBK1激酶就像一个刹车，限制了NLRP3途径的活性，而抑制TBK1的病毒通过移除这一途径的一个重要断裂来促进NLRP3驱动的炎症。我们现在提议描述我们发现背后的机制及其与当前大流行冠状病毒疾病的相关性。领导这项提议的团队由Pi(Jelena Bezbradica Mirkovic，她是巨噬细胞生物学、先天信号和炎症体方面的专家)、高效的炎症体专家博士后(Benjamin Demarco博士)将于2021年5月加入该团队；牛津大学的蛋白质组学合作者(Benedikt Kessler教授和Roman Fischer博士)以及肯尼迪大学世界领先的成像专家合作者(Michael Dustin教授)组成。关键的是，这项申请所依据的初步数据目前正在修订中，准备出版。

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.