Alt. symbols: NAK

Approved name: TANK binding kinase 1
Alt. names: TANK-binding kinase 1

Location: 12q14.2: 64452090 - 64502114 (+)
Gene type: protein_coding, 71 transcripts.

Scores: LoFtool: 0.541000 | pLI: 0.99509697 | LOEUF: 0.420

HGNC: 11584

NCBI: 29110, RefSeq: NG_046906.1

Ensembl: ENSG00000183735.11

LRG_1306 | Status: public

OMIM: 604834

Expression | ProteinAtlas

TBK1 encodes a ubiquitously expressed Ser/Thr kinase that acts upstream of both type I IFN signaling and NF-kappaB-dependent inflammatory cytokine production, and has been more recently implicated in the control of early autophagy and negative regulation of TNF-mediated RIPK1-dependent cell death (PMID: 34363755). In order to establish such an antiviral state, TBK1 forms several different complexes whose composition depends on the type of cell and immune stimulus. Several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1 can be recruited to the TBK1-containing-complexes. Upon toll-like receptor (TLR) activation by viral or bacterial components, TBK1 associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7, as well as DDX3X (PMID: 18583960). Subsequent IRF homodimerization and nuclear translocation leads to transcriptional activation of pro-inflammatory and antiviral genes, including IFNA and IFNB. TBK1 also phosphorylates NF-kappa-B inhibitor alpha (NFKBIA), IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PMID: 26999213). It can restrict bacterial proliferation by phosphorylating the autophagy receptor Optineurin (OPTN)to enhance LC3 binding affinity and antibacterial autophagy (PMID: 21617041). It also phosphorylates the SMCR8 component of the C9orf72-SMCR8 complex to promote autophagosome maturation (PMID: 28611593) and phosphorylates and activates AKT1. Moreover, it has been seen to attenuate retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PMID: 21270402).

Heterozygous TBK1 LOF missense mutations have been associated with susceptibility to Herpes simplex encephalitis (HSE) [OMIM: 617900] (PMID: 22851595). Herman et al. (2012) reported the first two cases of childhood HSE caused by heterozygous loss-of-function mutations in TBK1. The mutation p.D50A caused protein instability whereas the mutation p.G159A caused loss of kinase activity. Fibroblasts from both patients showed high viral replication and cell death rates caused by TL3-dependent viruses (HSV-1 and VSV). Moreover, fibroblasts from the patient with the G159A mutation showed defective poly(I:C)-induced TLR3 responses, despite intact IFN responses to TLR3-independent viruses and agonists in patient-derived fibroblasts and PBMCs. In 2015, Mork et al. identified an I207V mutation in an adult HSE case (50 year old female with HSV-2 infection) (PMID: 26513235). Monoallelic missense, splice-site or deletion mutations that result in TBK1 haploinsufficiency have been associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (FTDALS4), with significant intra-familial variation. FTD 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, while ALS is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. However, functional studies remain outstanding for these variants. More recently, homozygous LOF mutations have been identified in patients suffering from early-onset systemic autoinflammation likely exacerbated by viral infections, but with preserved anti-viral immunity (PMID: 34363755, 34210994). Clinical features included polyarthritis, vasculitis, recurrent fevers, growth failure, and neuro-inflammation manifesting as seizures, developmental delays, intellectual disability and evidence of brain atrophy on imaging (PMID: 34363755). Immunophenotyping of 2 affected patients showed activated and expanded CD4+ and CD8+ effector populations with reduced naive T and B cell populations and elevations of nonspecific pro-inflammatory cytokines. Taft et al. (2021) showed that autoinflammation in their patients was driven by TNF-induced RIPK1-driven necroptosis, consistent with the clinical responses patients showed to anti-TNF agents. [Load More]