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-kappaB and IRF3 transcription pathways to induce expression of
type I interferon (IFN-alpha and IFN-beta ) 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-beta, 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 TRAPbeta), which is a member of the
translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit
STING's ability to stimulate expression of IFN-beta. 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.