The innate immune kinase TBK1 phosphorylates and activates caspase-1 to enhance inflammasome-mediated inflammation

Caspase-1 is activated by inflammasomes, which drive its dimerization and auto-processing. Tight regulation of caspase-1 is essential to prevent pathological inflammation, yet the mechanisms controlling its auto-processing and enzymatic activity remain incompletely understood. Here, we identify TANK-binding kinase 1 (TBK1) as a novel regulator of caspase-1 activation. TBK1 directly interacts with caspase-1 and promotes its phosphorylation, and our mutagenesis data suggest that Thr307(mouse)/Thr309(human) may be involved in this regulation.Phosphorylation at this site enhances caspase-1 proteolytic function without affecting its dimerization. Notably, TBK1 is activated by diverse inflammasome triggers, whereas pharmacological inhibition of TBK1 suppresses caspase-1 activation and attenuates inflammasome-driven inflammation in vivo. Collectively, these findings identify the TBK1-caspase-1 axis as a previously unrecognized regulatory mechanism of inflammasome activation and suggest its potential relevance as a therapeutic target in inflammatory diseases.