Serine/threonine-protein kinase TBK1

Definition:

Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. 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. 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. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. 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. Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. 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. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation. Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes. Phosphorylates and activates AKT1. 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. Phosphorylates Borna disease virus (BDV) P protein. 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.

References:

[1]. Y Tojima, et al. NAK is an IkappaB kinase-activating kinase. Nature. 2000 Apr 13;404(6779):778-82. [Content Brief]

[2]. Adriana Goncalves, et al. Functional dissection of the TBK1 molecular network. PLoS One. 2011;6(9):e23971. [Content Brief]

[3]. Conggang Zhang, et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019 Mar;567(7748):394-398. [Content Brief]

[4]. Daqi Tu, et al. Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28;3(3):747-58. [Content Brief]

[5]. Amede Larabi, et al. Crystal structure and mechanism of activation of TANK-binding kinase 1. Cell Rep. 2013 Mar 28;3(3):734-46. [Content Brief]

[6]. Kristopher Clark, et al. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. [Content Brief]

[7]. Chang Shu, et al. Structural insights into the functions of TBK1 in innate antimicrobial immunity. Structure. 2013 Jul 2;21(7):1137-48. [Content Brief]

[8]. Sonia Sharma, et al. Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003 May 16;300(5622):1148-51. [Content Brief]

[9]. Katherine A Fitzgerald, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003 May;4(5):491-6. [Content Brief]

[10]. Philipp Wild, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011 Jul 8;333(6039):228-33. [Content Brief]

[11]. Qian Zhang, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4570. [Content Brief]

[12]. Yong Ran, et al. Autoubiquitination of TRIM26 links TBK1 to NEMO in RLR-mediated innate antiviral immune response. J Mol Cell Biol. 2016 Feb;8(1):31-43. [Content Brief]

[13]. Siqi Liu, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015 Mar 13;347(6227):aaa2630. [Content Brief]

[14]. Lina Herhaus, et al. TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. EMBO Rep. 2020 Jan 7;21(1):e48317. [Content Brief]

[15]. J L Pomerantz, et al. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 1999 Dec 1;18(23):6694-704. [Content Brief]

[16]. Xiaoduo Xie, et al. IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6474-9. [Content Brief]

[17]. Caitlyn T Hoffpauir, et al. TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection. J Immunol. 2020 Jul 1;205(1):153-167. [Content Brief]

[18]. Melina Herman, et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med. 2012 Aug 27;209(9):1567-82. [Content Brief]

[19]. Didier Soulat, et al. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008 Aug 6;27(15):2135-46. [Content Brief]

[20]. Chantal Sellier, et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 2016 Jun 15;35(12):1276-97. [Content Brief]

[21]. Qi Da, et al. TANK-binding kinase 1 attenuates PTAP-dependent retroviral budding through targeting endosomal sorting complex required for transport-I. J Immunol. 2011 Mar 1;186(5):3023-30. [Content Brief]

[22]. Holger Buss, et al. 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. 2004 Dec 31;279(53):55633-43. [Content Brief]

[23]. Mitsuaki Mori, et al. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J Biol Chem. 2004 Mar 12;279(11):9698-702. [Content Brief]

[24]. Gunhild Unterstab, et al. Viral targeting of the interferon-{beta}-inducing Traf family member-associated NF-{kappa}B activator (TANK)-binding kinase-1. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13640-5. [Content Brief]

[25]. Nandini Kishore, et al. IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. J Biol Chem. 2002 Apr 19;277(16):13840-7. [Content Brief]

[26]. Benjamin R tenOever, et al. Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J Virol. 2004 Oct;78(19):10636-49. [Content Brief]

[27]. Jun Kuai, et al. NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach. J Biol Chem. 2004 Dec 17;279(51):53266-71. [Content Brief]

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