STING recruits TBK1 and IRF3

Stable Identifier
R-HSA-1834939
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Vaccinia virus, Listeria monocytogenes, Human herpesvirus 1, Hepatitis B virus, Human immunodeficiency virus 1
Compartment
cytosol, cytoplasmic vesicle membrane
ReviewStatus
5/5
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STING recruits TBK1 and IRF3
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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
22394562 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway

Tanaka, Y, Chen, ZJ

Sci Signal 2012
22579474 Structural Analysis of the STING Adaptor Protein Reveals a Hydrophobic Dimer Interface and Mode of Cyclic di-GMP Binding

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

Immunity 2012
19926846 Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

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

Proc. Natl. Acad. Sci. U.S.A. 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

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

J Biol Chem 2002
19776740 STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

Ma, Z, Ishikawa, H, Barber, GN

Nature 2009
16306936 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response

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

Nature 2006
24560620 NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING

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

Immunity 2014
19433799 ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization

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

Proc. Natl. Acad. Sci. U.S.A. 2009
18818105 The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation

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

Immunity 2008
16281057 SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways

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

EMBO J 2005
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

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

J Exp Med 2004
Participants
Input
Output
Participates
as an event of
This event is regulated
Negatively by
Regulator
NLRC3 [cytosol] (Homo sapiens)
Regulator
TREX1 dimer [endoplasmic reticulum membrane] (Homo sapiens)
Positively by
Regulator
STING:cGAMP [cytoplasmic vesicle membrane] (Homo sapiens)
Active Unit
c-GMP-AMP [cytosol]
Regulator
dsDNA:IFI16 [cytosol] (Homo sapiens)
Regulator
DNA-PK:microbial dsDNA [cytosol] (Homo sapiens)
Regulator
MRE11:dsDNA [cytosol] (Homo sapiens)
Regulator
STING:c-di-GMP [cytoplasmic vesicle membrane] (Homo sapiens)
Active Unit
c-di-GMP [cytosol]
Regulator
DDX41:DDX41 ligand [cytosol] (Homo sapiens)
Regulator
DDX41:c-di-AMP, c-di-GMP [cytosol] (Homo sapiens)
Authored
Shamovsky, V  (2012-07-09)
Reviewed
D'Eustachio, P  (2012-07-18)
Jin, L  (2012-08-18)
Wu, J  (2013-05-22)
Created
Shamovsky, V  (2011-10-27)
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