TBK1

The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. [provided by RefSeq, Oct 2010]

TBK1 Gene(Protein Coding) TANK Binding Kinase 1

Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:10581243, PubMed:11839743, PubMed:15485837, PubMed:21138416, PubMed:25636800, PubMed:23453971, PubMed:23453972, PubMed:23746807, PubMed:26611359, PubMed:32404352).
Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:25636800).
This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995).
In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807).
Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653).
Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons (PubMed:25636800).
Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes (PubMed:21931631).
Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PubMed:10783893, PubMed:15489227).
Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041).
Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069).
Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes (PubMed:31709703).
Phosphorylates and activates AKT1 (PubMed:21464307).
Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity (By similarity).
Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402).
Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125).
Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595).

Activation of innate immune responseIEA:Ensembl
Defense response to Gram-positive bacteriumIEA:Ensembl
Defense response to virus3 PublicationsIC:ComplexPortal
Dendritic cell proliferationIEA:Ensembl
I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentTAS:UniProtKB
Inflammatory responseManual Assertion Based On ExperimentTAS:UniProtKB
Innate immune responseManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of gene expressionIEA:Ensembl
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-threonine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIEP:UniProtKB
Positive regulation of interferon-alpha productionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of interferon-beta productionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of macroautophagyManual Assertion Based On ExperimentIDA:HGNC
Positive regulation of peptidyl-serine phosphorylation1 PublicationNAS:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of type I interferon productionManual Assertion Based On ExperimentTAS:UniProtKB
Positive regulation of type I interferon-mediated signaling pathwayIEA:Ensembl
Positive regulation of xenophagyIEA:Ensembl
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of neuron death1 PublicationNAS:ParkinsonsUK-UCL
Regulation of type I interferon productionManual Assertion Based On ExperimentIDA:UniProtKB
Response to virusManual Assertion Based On ExperimentTAS:UniProtKB
Type I interferon signaling pathway2 PublicationsIC:ComplexPortal

Cytoplasm
Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2.

Glaucoma 1, open angle, P (GLC1P):
A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1P is characterized by early onset, thin central corneas and low intraocular pressure.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4):
A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis.
Encephalopathy, acute, infection-induced, 8, herpes-specific (IIAE8):
A rare, often fatal complication of herpes simplex infection, caused by virus spreading in the central nervous system. Disease manifestations include low-grade fever, severe headache, nausea, vomiting, and lethargy. Neurological features include confusion, acute memory disturbances, disorientation, behavioral changes, hemiparesis and seizures.

Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by PPM1B and this negatively regulates its role in mediating antiviral response.
'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401, participates in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAIP also leads to proteasomal degradation. 'Lys-63'-linked polyubiquitination by RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral responses.
(Microbial infection) Interaction with SARS-CoV-2 M protein induces 'Lys-48'-linked ubiquitination which leads to proteasomal degradation.