Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Genentech Inc, South San Francisco, USA.
Nat Commun. 2024 Jan 2;15(1):130. doi: 10.1038/s41467-023-44372-y.
TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.
TBK1 和 IKKε 调节多种细胞过程，包括抗病毒的 I 型干扰素反应、代谢和 TNF 受体信号转导。然而，IKKε 和 TBK1 在细胞死亡、炎症和组织稳态中的相对贡献和潜在冗余功能仍知之甚少。在这里，我们表明 IKKε 补偿了 TBK1 激酶活性的丧失，以防止小鼠中 RIPK1 依赖性和非依赖性炎症。IKKε 和 TBK1 激酶活性的联合抑制导致胚胎致死，而 RIPK1 激酶失活的杂合表达可挽救这一结果。表达激酶失活形式的 IKKε 和 TBK1 的成年小鼠会发生全身性炎症，这是由 RIPK1 依赖性和非依赖性机制共同诱导的。髓系细胞中 IKKε 和 TBK1 激酶活性的联合抑制会诱导 RIPK1 依赖性细胞死亡和由 IL-1 家族细胞因子介导的全身性炎症。组织特异性研究表明，IKKε 和 TBK1 需要防止肠道中的细胞死亡和炎症，但对肝脏和皮肤稳态是可有可无的。总之，这些发现表明 IKKε 和 TBK1 具有组织特异性功能，对于防止细胞死亡和炎症以及维持组织稳态至关重要。
