STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

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Abstract
Hiroki Ishikawa and Glen Barber report the identification of a molecule, STING (STimulator of INterferon Genes), that recognizes DNA and RNA virus infections and activates the body's innate immune system by triggering interferon production. STING, a previously uncharacterized protein, was isolated in an expression screen for its ability to activate the interferon-β promoter. It is located mainly in the endoplasmic reticulum and promotes interferon production via activation of the IRF3 and NF-κB pathways. It also interacts with RIG-I protein, a pattern recognition receptor involved in RNA virus detection, and with the translocon adaptor Sec61β, implicating the translocon or (the translocation channel involved in translocation of nascent polypeptides into the interior (cisternal or luminal) space of the endoplasmic reticulum in innate immune signalling. STING is an activator of IRF3 and NF-κB in response to RNA and DNA viruses. It localizes to the endoplasmic reticulum and interacts with both RIG-I and the translocon adaptor SEC61β implicating the translocon in innate immune signalling. 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.