STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling

By Hiroki Ishikawa, G. Barber. Nature, 2008

3,366 citations recorded by the source corpus.

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 translation. 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/321bb36c77cf099db072067eb5210f78072024fd

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Citations in the corpus

Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, positive): “138,139 Then, STING recruits tank-binding kinase 1 (TBK1), and inserts the C-terminal tail of STING inserts into TBK1 dimer.”
Cyclic GMP-AMP Synthase is Activated by Double-stranded DNA-Induced Oligomerization (2013, background): “The endoplasmic reticulum (ER) membrane-localized adaptor protein STING is essential for the responses to cytosolic DNA (Barber, 2011b; Ishikawa and Barber, 2008; Ishikawa et al., 2009; Sun et al., 2009; Zhong et al., 2009).”
The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells (2011, background): “Although the adaptor STING (also called TMEM173, ERIS, MPYS or MITA) has an essential role in sensing cytosolic DN”
IFI16 is an innate immune sensor for intracellular DNA (2010, background): “In addition to TBK1 and IRF3, a further critical downstream component of the response to intracellular DNA has been identified as STING (also called MITA, ERIS or TMEM173”
STING-dependent Cytosolic DNA Sensing Promotes Radiation-induced Type I interferon-dependent Antitumor Immunity in Immunogenic Tumors (2014, background): “In the past 6 years, STING has been demonstrated to be essential for the host protection against DNA pathogens through various mechanisms (Chen et al., 2011; Ishikawa and Barber, 2008; Ishikawa et al., 2009).”
Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1 (2014, methodology): “STING-deficient MEFs were described previously (4).”