Editors' ChoiceImmunology

Sense and Adapt

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Science Signaling  16 Apr 2013:
Vol. 6, Issue 271, pp. ec87
DOI: 10.1126/scisignal.2004243

Cells defend against bacterial and viral infection through the function of cytoplasmic DNA sensors that trigger the innate immune response. STING [stimulator of interferon (IFN) genes] is an endoplasmic reticulum adaptor protein that transmits signals between DNA-binding sensors DDX41 (DEAD box polypeptide 41) and IFI16 (interferon-inducible protein 16) and the effector kinase TBK1 to induce autophagosome recruitment. Abe et al. found that STING also functioned as a direct DNA sensor to induce the innate immune response. STING bound transfected viral and cellular DNA independently of DDX41 or IFI16 and was essential to trigger cytokine production [including type 1 IFN, CCL5, and TNF-α (tumor necrosis factor–α)] and the transcription of an array of genes involved in the innate immune response in human telomerase fibroblasts (hTERT-BJ1) and murine embryonic fibroblasts (MEFs). Knockdown of DDX41 or IFI16 did not affect the nuclear translocation of IRF3 (IFN regulatory factor 3) and NF-κB (nuclear factor κB) in response to transfected double-stranded DNA, whereas knockdown of STING prevented their translocation. In Sting–/– MEFs and 293T cells, which do not express STING, C-terminal mutants of STING were unable to bind cytoplasmic DNA, but either C- or N-terminal mutants were unable to induce transcription of type 1 IFN, suggesting that although the cytoplasmic tail of STING was essential for DNA binding, the conformation of intact STING was critical to its immune response function. Transfection of primary human or mouse cells with DNA triggered a greater STING-dependent response than did their transfection with cyclic di-guanosine monophosphate (di-GMP), a microbe-derived ligand that binds both STING and DDX41. The findings indicate that STING may have a dual function as both a sensor and adaptor in response to bacterial infection.

T. Abe, A. Harashima, T. Xia, H. Konno, K. Konno, A. Morales, J. Ahn, D. Gutman, G. N. Barber, STING recognition of cytoplasmic DNA instigates cellular defense. Mol. Cell 50, 5–15 (2013). [PubMed]