STING recruits TBK1 and IRF3

Stable Identifier
R-HSA-1834939
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Hepatitis B virus, Human immunodeficiency virus 1, Human herpesvirus 1, Listeria monocytogenes, Vaccinia virus
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In dsDNA-stimulated human and mouse cells TBK1 has been shown to move to cytoplasmic punctate structures, where it associates with STING to induce IRF3 activation (Ishikawa et al. 2009, Saitoh et al. 2009, Sun et al. 2009, Tanaka & Chen 2012). Co-immunoprecipitation assays in HEK 293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK1 directly interacts with STING. Moreover, glutathione S-transferase (GST) pull-down assays showed that recruitment of TBK1 by STING was enhanced upon c-di-GMP binding (Ouyang et al. 2012).

STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 (Zhong B et al. 2008, Tanaka and Chen 2012). Both TBK1 and IRF3 can directly interact with STING through its C-terminal region (Tanaka & Chen 2012). A construct of human STING containing only 39 amino acid residues of its C-terminus (341 to 379) was sufficient to activate IRF3 in cytosolic extracts of HeLa cells. Further mutagenesis studies showed, that two residues, Ser366 and Leu374, within the C-terminal tail of STING were required for IRF3 binding and phosphorylation, but were dispensable for TBK1 binding and activation (Tanaka & Chen 2012). Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. Importantly, though both STING monomers and dimers can bind TBK1, only STING dimers activates Type I IFN (Ouyang et al. 2012). The nucleotide binding domain and leucine-rich repeat-containing (NLR) protein NLRC3 interacts with STING and TBK1, reducing STING-TBK1 association and reduces the trafficking of STING to the perinuclear region, leading to decreased activation of innate immune cytokines (Zhang et al. 2014).

Literature References
PubMed ID Title Journal Year
16281057 SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways

Huang, J, Liu, T, Xu, LG, Chen, D, Zhai, Z, Shu, HB

EMBO J 2005
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and

Hemmi, H, Takeuchi, O, Sato, S, Yamamoto, M, Kaisho, T, Sanjo, H, Kawai, T, Hoshino, K, Takeda, K

J Exp Med 2004
18818105 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation

Zhong, B, Yang, Y, Li, S, Wang, YY, Li, Y, Diao, F, Lei, C, He, X, Zhang, L, Tien, P, Shu, HB

Immunity 2008
19433799 ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

Sun, W, Li, Y, Chen, L, Chen, H, You, F, Zhou, X, Zhou, Y, Zhai, Z, Chen, D, Jiang, Z

Proc. Natl. Acad. Sci. U.S.A. 2009
24560620 NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING

Zhang, L, Mo, J, Swanson, KV, Wen, H, Petrucelli, A, Gregory, SM, Zhang, Z, Schneider, M, Jiang, Y, Fitzgerald, KA, Ouyang, S, Liu, ZJ, Damania, B, Shu, HB, Duncan, JA, Ting, JP

Immunity 2014
16306936 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response

Oganesyan, G, Saha, SK, Guo, B, He, JQ, Shahangian, A, Zarnegar, B, Perry, A, Cheng, G

Nature 2006
19776740 STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

Ishikawa, H, Ma, Z, Barber, GN

Nature 2009
12133833 Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases

Chariot, A, Leonardi, A, Muller, J, Bonif, M, Brown, K, Siebenlist, U

J Biol Chem 2002
19926846 Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

Saitoh, T, Fujita, N, Hayashi, T, Takahara, K, Satoh, T, Lee, H, Matsunaga, K, Kageyama, S, Omori, H, Noda, T, Yamamoto, N, Kawai, T, Ishii, K, Takeuchi, O, Yoshimori, T, Akira, S

Proc. Natl. Acad. Sci. U.S.A. 2009
22579474 Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding

Ouyang, S, Song, X, Wang, Y, Ru, H, Shaw, N, Jiang, Y, Niu, F, Zhu, Y, Qiu, W, Parvatiyar, K, Li, Y, Zhang, R, Cheng, G, Liu, ZJ

Immunity 2012
22394562 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway

Tanaka, Y, Chen, ZJ

Sci Signal 2012
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