Letter | Published:

STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

Nature volume 455, pages 674678 (02 October 2008) | Download Citation

Subjects

  • A Corrigendum to this article was published on 13 November 2008

Abstract

The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response—following infection with DNA and RNA viruses, for example—remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-κB and IRF3 transcription pathways to induce expression of type I interferon (IFN-α and IFN-β ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-β, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPβ), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation1,2. Ablation by RNA interference of both TRAPβ and translocon adaptor SEC61β was subsequently found to inhibit STING’s ability to stimulate expression of IFN-β. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. A tetrameric complex of membrane proteins in the endoplasmic reticulum. Eur. J. Biochem. 214, 375–381 (1993)

  2. 2.

    et al. Architecture of the ribosome-channel complex derived from native membranes. J. Mol. Biol. 348, 445–457 (2005)

  3. 3.

    & Recognition of viruses by innate immunity. Immunol. Rev. 220, 214–224 (2007)

  4. 4.

    et al. Genetic analysis of resistance to viral infection. Nature Rev. Immunol. 7, 753–766 (2007)

  5. 5.

    et al. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol. Cell 29, 428–440 (2008)

  6. 6.

    et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006)

  7. 7.

    et al. 5'-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006)

  8. 8.

    et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004)

  9. 9.

    et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 82, 335–345 (2008)

  10. 10.

    , & Regulation of antiviral innate immune responses by RIG-I family of RNA helicases. Curr. Top. Microbiol. Immunol. 316, 193–205 (2007)

  11. 11.

    et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature Immunol. 6, 981–988 (2005)

  12. 12.

    et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005)

  13. 13.

    et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005)

  14. 14.

    et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19, 727–740 (2005)

  15. 15.

    et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl Acad. Sci. USA 101, 233–238 (2004)

  16. 16.

    , & A FADD-dependent innate immune mechanism in mammalian cells. Nature 432, 401–405 (2004)

  17. 17.

    et al. VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway. Mol. Cell 17, 93–102 (2005)

  18. 18.

    et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006)

  19. 19.

    et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40–48 (2006)

  20. 20.

    & Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006)

  21. 21.

    & The exocyst meets the translocon: A regulatory circuit for secretion and protein synthesis? Trends Cell Biol. 14, 61–63 (2004)

  22. 22.

    , & The exocyst affects protein synthesis by acting on the translocation machinery of the endoplasmic reticulum. J. Biol. Chem. 278, 20954–20960 (2003)

  23. 23.

    et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127, 157–170 (2006)

  24. 24.

    et al. Fas-associated death domain-containing protein-mediated antiviral innate immune signaling involves the regulation of Irf7. J. Immunol. 178, 2429–2439 (2007)

  25. 25.

    et al. Processing of human cytomegalovirus UL37 mutant glycoproteins in the endoplasmic reticulum lumen prior to mitochondrial importation. J. Virol. 80, 6771–6783 (2006)

Download references

Acknowledgements

We thank T. Venkataraman, J. Hyun, T. Sato and M. Conkright for technical assistance, M. Gale for RIG-I and IPS-1 lacking MEFs, Y. C. Weh for TBK-1 lacking MEFs, and S. Nagata, T. Maniatis, J. Hiscott and N. Reich for plasmid constructs.

Author information

Affiliations

  1. Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA

    • Hiroki Ishikawa
    •  & Glen N. Barber

Authors

  1. Search for Hiroki Ishikawa in:

  2. Search for Glen N. Barber in:

Corresponding author

Correspondence to Glen N. Barber.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Figures 1-9 with Legends.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature07317

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.