AMPK directly phosphorylates TBK1 to integrate glucose sensing into innate immunity

Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglyce-mia 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.

Automated summary

This study found that viral infection leads to a rapid decrease in blood glucose levels, resulting in the activation of AMPK. The activated AMPK directly phosphorylates TBK1, triggering the recruitment of IRF3 and the assembly of MAVS or STING signalosomes. However, depletion or inhibition of AMPK and increased glucose levels impair nucleic acid sensing, while enhancing the AMPK-TBK1 cascade significantly improves antiviral immunity.