MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Acta Biochim Biophys Sin (Shanghai). 2020 Jul 10;52(7):757-767. doi: 10.1093/abbs/gmaa051.
Sensing of intracellular and extracellular environments is one of the fundamental processes of cell. Surveillance of aberrant nucleic acids, derived either from invading pathogens or damaged organelle, is conducted by pattern recognition receptors (PRRs) including RIG-I-like receptors, cyclic GMP-AMP synthase, absent in melanoma 2, and a few members of toll-like receptors. TANK-binding kinase 1 (TBK1), along with its close analogue I-kappa-B kinase epsilon, is a central kinase in innate adaptor complexes linking activation of PRRs to mobilization of transcriptional factors that transcribe proinflammatory cytokines, type I interferon (IFN-α/β), and myriads interferon stimulated genes. However, it still remains elusive for the precise mechanisms of activation and execution of TBK1 in signaling platforms formed by innate adaptors mitochondrial antiviral signaling protein (MAVS), stimulator of interferon genes protein (STING), and TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as its complex regulations. An atlas of TBK1 substrates is in constant expanding, setting TBK1 as a key node of signaling network and a dominant player in contexts of cell biology, animal models, and human diseases. Here, we review recent advancements of activation, regulations, and functions of TBK1 under these physiological and pathological contexts.
细胞内和细胞外环境的感应是细胞的基本过程之一。模式识别受体 (PRRs) 包括 RIG-I 样受体、环鸟苷酸-AMP 合酶、黑色素瘤 2 缺失蛋白和几个 Toll 样受体，可对源自入侵病原体或受损细胞器的异常核酸进行监测。TANK 结合激酶 1 (TBK1) 及其密切相关的 IκB 激酶 ε 是连接 PRR 激活和转录因子动员的先天衔接复合物中的核心激酶，这些转录因子可转录促炎细胞因子、I 型干扰素 (IFN-α/β) 和无数干扰素刺激基因。然而，对于先天衔接子线粒体抗病毒信号蛋白 (MAVS)、干扰素基因刺激蛋白 (STING) 和 TIR 结构域包含衔接子诱导 IFN-β (TRIF) 形成的信号平台中 TBK1 的激活和执行的精确机制以及其复杂的调控，目前仍难以捉摸。TBK1 底物图谱不断扩大，TBK1 作为信号网络的关键节点和细胞生物学、动物模型和人类疾病背景下的主要调控因子。在此，我们综述了 TBK1 在这些生理和病理背景下的激活、调控和功能的最新进展。
