STING mediated induction of host immune responses

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Homo sapiens
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STING (stimulator of IFN genes; also known as MITA/ERIS/MPYS/TMEM173) is an endoplasmic reticulum (ER) resident, which is required for effective type I IFN production in response to nucleic acids. Indeed, select pathogen-derived DNA or RNA were shown to activate STING in human and mouse cells (Ishikawa H and Barber GN 2008; Ishikawa H et al. 2009; Sun W et al. 2009; Prantner D et al. 2010). Importantly, in vitro studies have shown that STING is essential for Mycobacterium tuberculosis (Manzanillo PS et al. 2012), Plasmodium falciparum (Sharma S et al. 2011) and human immunodeficiency virus (HIV) induced type I IFN production [Yan N et al 2010]. Mycobacterium tuberculosis, plasmodium falciparum and HIV are three deadliest pathogens, which kill millions of people each year worldwide.

STING has been also implicated in type I IFN response which was stimulated by fusion of viral and target-cell membrane in a manner independent of DNA, RNA and viral capsid [Holm CK et al 2012].

Under steady state conditions, STING is positioned at the translocon complex within the ER membrane. However upon stimulation with intracellular DNA it translocates from ER to perinuclear vesicles via the Golgi by mechanisms that remain unclear (Ishikawa H and Barber GN 2008; Sun W et al. 2009; Ishikawa H et al. 2009; Saitoh T et al. 2009). Mouse Sting trafficking in dsDNA-stimulated mouse embryonic fibroblasts (MEF) cells was found to depend on autophagy-related gene 9a (Atg9a) (Saitoh T et al. 2009).

STING was reported to function as a signaling adaptor or coreceptor in response to cytosolic dsDNA (Unterholzner L et al. 2010; Zhang Z et al. 2011). STING was also shown to function as a direct DNA sensor to induce the innate immune response in human telomerase fibroblasts (hTERT-BJ1) and murine embryonic fibroblasts (MEFs) (Abe T et al. 2013). Additionally, STING is thought to function as a direct sensor of cyclic dinucleotides. STING was shown to interact directly with c-di-GMP in human embryonic kidney HEK293T cell lysates (Burdette DL et al. 2011). Once STING is stimulated, its C-terminus serves as a signaling scaffold to recruit IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3 (Tanaka Y and Chen ZJ 2012).

Mouse, but not human STING, can also bind vascular disrupting agents 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and the antiviral small molecule 10-carboxymethyl-9-acridanone (CMA) to induce type I IFN production, suggesting a species-specific drug effect on the STING-mediated host response (Conlon J et al. 2013; Cavlar T et al. 2013).

Literature References
PubMed ID Title Journal Year
22607800 Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages

Cox, JS, Manzanillo, PS, Shiloh, MU, Portnoy, DA

Cell Host Microbe 2012
23478444 STING Recognition of Cytoplasmic DNA Instigates Cellular Defense

Konno, H, Ahn, J, Harashima, A, Morales, A, Xia, T, Abe, T, Konno, K, Barber, GN, Gutman, D

Mol. Cell 2013
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
23604073 Species-specific detection of the antiviral small-molecule compound CMA by STING

Ablasser, A, Hopfner, KP, Cavlar, T, Hornung, V, Deimling, T

EMBO J. 2013
20107183 Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection

Nagarajan, UM, Darville, T, Prantner, D

J. Immunol. 2010
18724357 STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

Ishikawa, H, Barber, GN

Nature 2008
23585680 Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid

Burdette, DL, Fitzgerald, KA, Sharma, S, Vance, RE, Bhat, N, Conlon, J, Xiao, TS, Monks, B, Rathinam, VA, Jin, T, Thompson, M, Vogel, SN, Jiang, Z

J. Immunol. 2013
22706339 Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING

Fitzgerald, KA, Rasmussen, SB, Herold, BC, Gonzalez-Dosal, R, Holm, CK, Rixon, FJ, Horan, KA, Jakobsen, MR, Yarovinsky, TO, Paludan, SR, Jensen, SB, Cheshenko, N, Moeller, HB, Christensen, MH

Nat. Immunol. 2012
21892174 The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells

Yuan, B, Lu, N, Kim, T, Zhang, Z, Liu, YJ, Bao, M

Nat. Immunol. 2011
21947006 STING is a direct innate immune sensor of cyclic di-GMP

Burdette, DL, Eckert, B, Vance, RE, Hayakawa, Y, Iwig, JS, Sotelo-Troha, K, Hyodo, M, Monroe, KM

Nature 2011
21820332 Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome

Fitzgerald, KA, Sharma, S, Barber, GN, Hall, JP, Gazzinelli, RT, Goutagny, N, Kalantari, P, DeOliveira, RB, Lauw, F, Chan, J, Golenbock, DT, Jiang, Z, Parroche, P, Bartholomeu, DC

Immunity 2011
19776740 STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

Ma, Z, Ishikawa, H, Barber, GN

Nature 2009
20871604 The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1

Lieberman, J, Yan, N, Regalado-Magdos, AD, Lee-Kirsch, MA, Stiggelbout, B

Nat. Immunol. 2010
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
20890285 IFI16 is an innate immune sensor for intracellular DNA

Xiao, TS, Fitzgerald, KA, Sharma, S, Latz, E, Sirois, CM, Horan, KA, Bowie, AG, Keating, SE, Unterholzner, L, Baran, M, Jin, T, Jensen, SB, Paludan, SR

Nat Immunol 2010
22394562 STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway

Tanaka, Y, Chen, ZJ

Sci Signal 2012
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