TBK1 gene

The TBK1 gene (TBK1 stands for TANK binding kinase 1) is a protein-coding gene located on chromosome 12q14.2. Molecular activities associated with this gene include nucleic acid binding and protein kinase activity. The signaling pathways associated with the TKK1 gene include the Toll-like receptor 7/8 cascade (TLR7/8) and cytosolic sensors for pathogen-associated DNA. An important paralog of this gene is the IKBKE gene.

The TBK1 gene encodes a kinase of the same name, a serine/threonine kinase, which plays an essential role in the regulation of inflammatory reactions to foreign substances (Pomerantz JL et al. 1999; Fitzgerald KA et al. 2003). After activation of Toll-like receptors by viral or bacterial components, it binds to TRAF3 and TANK and phosphorylates the interferon-regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (Mori M et al. 2004). This activity enables subsequent homodimerization and nuclear translocation of the IRFs, leading to transcriptional activation of proinflammatory and antiviral genes including IFNA and IFNB (Fitzgerald KA et al. 2003) To establish such an antiviral state, TBK1 forms several different complexes whose composition depends on the type of cell and the cellular stimuli.

The TBK! kinase plays a key role in the activation of IRF3 and acts by first phosphorylating the innate adapter proteins MAVS, STING1 and TICAM1 at their pLxIS motif, which leads to the recruitment of IRF3 and thereby licenses IRF3 for phosphorylation by TBK1. Phosphorylated IRF3 detaches from the adapter proteins, dimerizes and then enters the nucleus to induce expression of interferons (PubMed:25636800). Thus, several scaffold molecules, including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD, can be recruited to the TBK1-containing complexes. Under certain conditions, it functions as an NF-kappa-B effector by phosphorylating the NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to transport NF-kappa-B into the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/optineurin on "Ser-177", thereby increasing LC3 binding affinity and antibacterial autophagy. Phosphorylates the SMCR8 component of the C9orf72-SMCR8 complex and thus promotes the maturation of autophagosomes. Phosphorylates the ATG8 proteins MAP1LC3C and GABARAPL2, preventing their delipidation and premature removal from nascent autophagosomes.

Appears to play a role in regulating energy balance by maintaining a state of chronic, low-grade inflammation in obesity, negatively impacting insulin sensitivity (By similarity). Reduces retroviral budding by phosphorylating the endosomal sorting complex required for the transport I (ESCRT-I) subunit VPS37C. Phosphorylates the P protein of Borna virus (BDV). Plays an essential role in TLR3- and IFN-dependent control of HSV-1 and HSV-2 infections in the central nervous system. Acts as both a positive and negative regulator of the mTORC1 complex depending on context: Activates mTORC1 in response to growth factors by catalyzing the phosphorylation of MTOR, while limiting the mTORC1 complex by promoting the phosphorylation of RPTOR.

Acts as a positive regulator of the mTORC2 complex by mediating the phosphorylation of MTOR, leading to increased phosphorylation and activation of AKT1. Phosphorylates and activates AKT1 (Xie X et al.2011). The kinase is involved in the regulation of TNF-induced RIPK1-mediated cell death, probably via CYLD phosphorylation, which in turn controls the ubiquitination status of RIPK1. Also participates in the differentiation of follicular regulatory T cells (Treg) together with the receptor ICOS.

Diseases associated with TBK1 include acute infectious encephalopathy 8 and frontotemporal dementia and/or amyotrophic lateral sclerosis 4.

1. Buss H et al. (2004) Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem 279:55633-43.
2. Fitzgerald KA et al. (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491-496.
3. Mori M et al. (2004) Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J Biol Chem 279:9698-9702.
4. Pomerantz JL et al. (1999) NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J 18:6694-704.
5. Xie X et al.(2011) IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A 108):6474-659