TBK1, Serine/threonine-protein kinase TBK1
Enzyme Classification 18.104.22.168
Also Known as
TBK1_HUMAN, TBK1, NAK
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). 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). 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, TMEM173/STING 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 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). Homodimer (PubMed:21145761). Interacts with DDX3X, TIRAP and TRAF2 (PubMed:10581243, PubMed:14530355). Part of a ternary complex consisting of TANK, TRAF2 and TBK1 (PubMed:10581243). Interacts with AZI2, TANK and TBKBP1; these interactions are mutually exclusive and mediate TBK1 activation (PubMed:14560022, PubMed:21931631, PubMed:23453972, PubMed:10581243). Interacts with GSK3B; this interaction promotes TBK1 self-association and autophosphorylation (PubMed:21145761). Interacts with SIKE1; SIKE1 is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation (PubMed:16281057). Interacts with IRF3, leading to IRF3 phosphorylation (PubMed:14703513, PubMed:25636800). Interacts with DDX58/RIG-I (PubMed:16281057). Interacts with CYLD (PubMed:18636086). Interacts with OPTN and TRAF3 (PubMed:20174559). Interacts with SRC (PubMed:19419966). Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity (PubMed:17018283). Interacts with TMEM173/STING, leading to TMEM173/STING phosphorylation (PubMed:19416887, PubMed:25636800, PubMed:30842653). Interacts with IFIT3 (via N-terminus) (PubMed:21813773). Interacts with MAVS; interaction only takes place in the presence of IFIT3 and leads to MAVS phosphorylation (PubMed:21813773, PubMed:25636800). Interacts with TICAM1; this interaction is enhanced in the presence of WDFY1 and leads to TICAM1 phosphorylation (PubMed:14530355, PubMed:14739303, PubMed:25736436, PubMed:25636800). Interacts with TRIM26 (PubMed:26611359). Interacts with TRIM23 (PubMed:28871090).