TBK1 Summary

TBK1 (Tank-binding kinase 1) is a serine/threonine kinase essential for innate immune signaling, particularly in controlling inflammatory and antiviral responses (UniProt: Q9UHD2). Upon toll-like receptor activation, it associates with TRAF3 and TANK to phosphorylate interferon regulatory factors IRF3 and IRF7, driving transcription of type I interferons and pro-inflammatory genes. Beyond inflammation, TBK1 regulates selective autophagy by phosphorylating autophagy receptors and ATG8 proteins, and modulates mTORC1/2 signaling and TNF-induced cell death through multiple substrate interactions.

TBK1 is expressed broadly and has established roles in central nervous system antiviral defense, particularly against HSV infections (UniProt: Q9UHD2). Pathogenic variants associate with frontotemporal dementia and/or amyotrophic lateral sclerosis (FTDALS4), glaucoma, and herpes-specific encephalopathy, reflecting its importance in neuroinflammation and neuroprotection.

In Alzheimer's disease, TBK1 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.47 (Chaparral AD proteomics). This reduction may impair innate immune responses and autophagy-mediated clearance of pathogenic protein aggregates, potentially contributing to AD pathology.