AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity

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. [Display omitted] •Viral infection induces acute blood glucose decline in rodents that activates AMPK•AMPK directly phosphorylates TBK1 at S511 to prime antiviral sensing•AMPK-TBK1 couples glucose deficiency sensing and innate immune surveillance•Targeting the AMPK-TBK1 axis compromises innate antiviral immunity The relevance between blood glucose levels and antiviral defense is long appreciated, but not its molecular basis. Zhang et al. identify an inherent function of the energy regulator AMPK, which couples glucose and nucleic acid dual sensing via an elegant AMPK-TBK1 cascade and connects physiological glucose levels to antiviral immunity.