TBK1

TBK1, short for TANK-binding kinase 1, is a serine/threonine protein kinase that mediates key signaling events in the innate immune system. It is encoded by the TBK1 gene in humans and is conserved across vertebrates. The enzyme integrates signals from multiple pattern recognition receptors to coordinate inflammatory and antiviral responses.

In cellular signaling, TBK1 transduces cues from toll-like receptors, particularly TLR3 and TLR4, via the adaptor TRIF, as well as from RIG-I-like receptors through MAVS. This convergence leads to activation of transcription factors such as IRF3 and NF-κB, resulting in the production of type I interferons and pro-inflammatory cytokines. TBK1 also functions downstream of the cGAS-STING pathway in response to cytosolic DNA. Beyond cytokine induction, TBK1 participates in autophagy by phosphorylating selective autophagy receptors like OPTN and p62, promoting xenophagy and mitophagy.

Structurally, TBK1 contains an N-terminal kinase domain, a central ubiquitin-like domain, and C-terminal coiled-coil regions that mediate dimerization and interactions with adaptor proteins. Activation typically requires recruitment to signaling complexes and autophosphorylation of the activation loop, notably at Ser172. Adaptor proteins such as TANK, SINTBAD, and NAP1, along with ubiquitin signaling, regulate TBK1 activity. TBK1 can also be activated downstream of STING in DNA sensing pathways.

Clinical significance includes associations between TBK1 dysfunction and neurodegenerative diseases, particularly amyotrophic lateral sclerosis and frontotemporal dementia, often through reduced gene dosage. Variants in TBK1 have been studied in inflammatory diseases and cancer as well. Because of its central role in innate immunity and autophagy, TBK1 is a target of pharmacological inhibitors being explored to modulate immune responses in various diseases.