Disease relevance of TBK1

• In the present study, we examine the activation of TBK1 and IKKepsilon kinases by vesicular stomatitis virus (VSV) infection in human lung epithelial A549 cells [1].
• Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response [2].
• Fluorescence in situ hybridization using full-length human NAK cDNA as a probe showed that the human NAK gene is localized to human chromosome 13q14.2-3, a region in which the loss of heterozygosity is associated with squamous cell carcinoma and leukemia [3].
• The activation of Nef-associated kinase (NAK) by Nef from human and simian immunodeficiency viruses is critical for efficient viral replication and pathogenesis [4].
• The role of NAK association is currently not known but it has been implicated in enhanced viral infectivity in cell culture and in disease progression in SIV-infected macaques [3] [5].

High impact information on TBK1

• RalB GTPase-Mediated Activation of the IkappaB Family Kinase TBK1 Couples Innate Immune Signaling to Tumor Cell Survival [6].
• In tumor cells the RalB/TBK1 pathway inhibits apoptosis and in nontumorigenic cells it stimulates an innate immune response [7].
• B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi [8].
• IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway [9].
• These include the kinase TBK1 as well as Toll-like receptor adaptor molecule and IFN regulatory factor 3 [10].

Chemical compound and disease context of TBK1

• Nef proteins from human immunodeficiency virus type 1 isolate SF2 (HIV-1SF2) and simian immunodeficiency virus isolate mac239 (SIVmac239) have been found to associate with a cellular serine/threonine kinase designated NAK [11].

Biological context of TBK1

• These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders [8].
• We conclude that TBK1 is essential for IRF3-dependent antiviral gene expression [12].
• Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway [10].
• The protein kinase TBK1 is a key regulator inducing phosphorylation of IRF3 [13].
• In addition to TBK1 and IKKepsilon, our results indicate that IKKbeta can also phosphorylate IRF-3 and activate the IFN-stimulated response element [14].

Anatomical context of TBK1

• This pattern of expression and the decreased expression of angiogenic factors in cultured cells upon RNA-interference-mediated ablation suggests that TBK1 is important for vascularization and subsequent tumor growth and a target for cancer therapy [10].
• These data suggest that intracellular RNP formation contributes to the early recognition of VSV infection, activates the catalytic activity of TBK1, and induces transcriptional upregulation of IKKepsilon in epithelial cells [1].
• In addition, no degradation of IRF-3 was observed in TBK1(-/-) mouse embryonic fibroblasts [15].
• Virus-induced Viperin expression was not attenuated in macrophages deficient in either TBK1 or IKKepsilon alone [16].
• We further showed that NAK is recruited to TNFR1 in a temporally regulated and TNFalpha-dependent manner and that it mediates the TNFalpha-induced production of the chemokine RANTES (regulated on activation normal T cell expressed and secreted) [17].

Associations of TBK1 with chemical compounds

• Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission [18].
• Previously, we and others demonstrated that Nef associates with a cellular serine kinase (NAK) activity [19].
• The low molecular weight yellow pigment in the gray squirrel lens is confirmed to be n-acetyl-3-OH-kynurenine (NAK) [20].

Enzymatic interactions of TBK1

• IKK-related kinases TBK1 and IKKepsilon have been shown to phosphorylate and activate IRF-3 and IRF-7, leading to the production of type 1 interferons and the development of a cellular antiviral state [21].

Regulatory relationships of TBK1

• NAP1 activates NAK and facilitates its oligomerization [22].
• NAK has been identified as an IkappaB-kinase activating-kinase that plays an important role in NF-kappaB activation in response to several pro-inflammatory cytokines such as TNF-alpha [3].
• The importance of the ULD of TBK1 in LPS- or poly(I:C)-stimulated IFN-beta production was demonstrated by reconstitution experiments in TBK1-IKK-i-deficient cells [23].

Other interactions of TBK1

• Here we show that TBK1 and IKK epsilon synergize with TANK to promote interaction with the IKKs [24].
• TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway [14].
• An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity [2].
• We examined the phosphorylation and activation of IRF-5 by TBK1 and IKKepsilon kinases [21].
• IkappaBalpha and TBK1 mRNA were increased in the perimenstrual phase of the menstrual cycle [25].

References