Innate immunity: STING: adding to the antiviral arsenal

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STING (stimulator of interferon (IFN) genes) is an ER adaptor protein that mediates host responses to pathogen-derived nucleic acids.

A study published in Nature has characterized a previously unidentified protein that is essential for effective innate immune signalling processes and, in particular, for optimal host defence against several types of virus.

This protein, known as STING (stimulator of interferon (IFN) genes), was identified in a screen of human proteins that could activate the IFNB promoter. Additional experiments showed that STING achieved this by inducing the activation of other factors that are central to triggering the innate antiviral response, such as IFN-regulatory factor 3 and nuclear factor- kappa B. In further support of a role for STING in mounting effective antiviral cellular responses, transfection of mouse embryonic fibroblasts with STING rendered them resistant to infection with vesicular stomatitis virus (VSV; a negative-stranded RNA virus), whereas the inhibition of STING expression in human embryonic kidney 293 cells markedly increased their susceptibility to VSV.

Comparison of STING-deficient and wild-type fibroblasts confirmed that STING is essential for optimal IFN beta production in response to VSV infection. However, STING was not required, at least in vitro, for IFN beta production in response to encephalomyocarditis virus, a positive-stranded RNA virus that is recognized through a pathway that is dependent on the intracellular sensor MDA5 (melanoma-differentiation-associated gene 5). Co-precipitation and microscopy analyses indicated that STING physically interacts with RIG-I (retinoic-acid-inducible gene I) but not MDA5, and that it acts downstream of RIG-I. So, STING seems to have an important downstream function in facilitating RIG-I-mediated detection of negative-stranded RNA viruses.

In addition to its role in the recognition of RNA, STING was also found to be involved in the detection of DNA. When compared with wild-type cells, STING-deficient cells were found to be profoundly defective at inducing the expression of IFN beta in response to the DNA virus herpes simplex virus 1 or to bacteria. The authors also showed that the action of STING did not influence the activation of the Toll-like-receptor signalling pathway, which can also be triggered in response to viral nucleic acids and other pathogen-associated molecules.

Microscopy and fractionation experiments showed that STING predominantly localized to the endoplasmic reticulum (ER), where it was found to physically associate with the TRAP (translocon-associated protein) complex that transports newly translated proteins across the ER membrane. When the expression of proteins that are required for TRAP-complex assembly was inhibited, the capacity of STING to induce IFN beta production was lost.

Together, these data characterize STING as an ER adaptor protein that mediates responses to pathogen-derived nucleic acids and provide evidence that the ER translocon complex might be important for efficient induction of IFN beta in response to viral infection.

Sarah Allan

References

Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008) | Article | PubMed |