TBK1

TBK1 (TANK-binding kinase 1) is a cytoplasmic non-canonical IKB kinase (IKK)-related serine/threonine protein kinase. Its domain architecture comprises an N-terminal protein kinase domain, a ubiquitin-like domain (ULD), a scaffold/dimerization domain, and a C-terminal coiled-coil region that mediates homodimerization; the active kinase is generated by trans-autophosphorylation at Ser172. TBK1 is a master kinase of innate antiviral immunity: downstream of cytoplasmic nucleic-acid sensors (RIG-I/MDA5 via MAVS; cGAS via STING1) and endosomal Toll-like receptors (TLR3/TLR4 via TRIF/TICAM1), TBK1 phosphorylates these adaptor proteins on their pLxIS motif to recruit and then phosphorylate the transcription factors IRF3 and IRF7, driving their dimerization, nuclear translocation, and induction of type I interferons (IFN-alpha/IFN-beta) and other antiviral/pro-inflammatory genes. It is the kinase effector of the cGAS-STING DNA-sensing pathway and was originally identified as an NF-kappaB-activating kinase (binding the adaptor TANK), phosphorylating RELA/NFKBIA/IKBKB under particular conditions. TBK1 is also a central kinase of selective autophagy: it phosphorylates the autophagy cargo receptors OPTN/optineurin (Ser177), SQSTM1/p62, NDP52/CALCOCO2 and TAX1BP1 to enhance their ubiquitin- and LC3-binding and drive mitophagy and antibacterial xenophagy, and it phosphorylates SMCR8 (in the C9orf72-SMCR8 complex) and the ATG8 proteins MAP1LC3C and GABARAPL2 to promote autophagosome maturation. TBK1 assembles into kinase complexes with scaffolding adaptors AZI2/NAP1, TANK and TBKBP1/SINTBAD. Additional context-dependent roles include bidirectional regulation of mTORC1/mTORC2 signaling, AKT1 activation, and immune cell differentiation. TBK1 activity is antagonized by numerous viral proteins, and human mutations cause familial ALS/frontotemporal dementia (haploinsufficiency), normal-tension/primary open-angle glaucoma, herpes-simplex encephalopathy, and autoinflammatory disease.

Disorders

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• disabled_macroautophagy via Amyotrophic Lateral Sclerosis
• viral_neural_progenitor_cytopathy named in the module itself