The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China; Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University (HIC-ZJU), Hangzhou 310058, China; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China.
The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China; Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University (HIC-ZJU), Hangzhou 310058, China.
Mol Cell. 2022 Dec 1;82(23):4519-4536.e7. doi: 10.1016/j.molcel.2022.10.026. Epub 2022 Nov 15.
Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes. Consistently, ablation or inhibition of AMPK, knockin of TBK1-S511A, or increased glucose levels compromised nucleic acid sensing, while boosting AMPK-TBK1 cascade by AICAR or TBK1-S511E knockin improves antiviral immunity substantially in various animal models. Thus, we identify TBK1 as an AMPK substrate, reveal the molecular mechanism coupling a dual sensing of glucose and nuclei acids, and report its physiological necessity in antiviral defense.
营养感应和损伤感应是生物体内的两个基本过程。虽然高血糖通常与糖尿病相关的微生物易感性有关，但机体葡萄糖水平如何影响先天免疫对微生物入侵的反应还不完全清楚。在这里，我们惊讶地发现，病毒感染导致啮齿动物的血糖水平迅速而显著下降，导致 AMPK 强烈激活。一旦 AMPK 被激活，它就会直接在 S511 位磷酸化 TBK1，从而触发 IRF3 的募集和 MAVS 或 STING 信号小体的组装。一致地，AMPK 的缺失或抑制、TBK1-S511A 的敲入或葡萄糖水平的增加损害了核酸感应，而通过 AICAR 或 TBK1-S511E 敲入来增强 AMPK-TBK1 级联反应，在各种动物模型中显著改善了抗病毒免疫。因此，我们确定 TBK1 是 AMPK 的底物，揭示了葡萄糖和核酸双感应的分子机制，并报告了其在抗病毒防御中的生理必要性。
