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

Correspondence to: Glen N. Barber¹ Correspondence and requests for materials should be addressed to G.N.B. (Email: gbarber@med.miami.edu).

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-B and IRF3 transcription pathways to induce expression of type I interferon (IFN- and IFN- ) 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-, 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 TRAP), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation^{1, 2}. Ablation by RNA interference of both TRAP and translocon adaptor SEC61 was subsequently found to inhibit STING's ability to stimulate expression of IFN-. 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.

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