Sci Signal
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Cytosolic pattern recognition receptors (PRRs) sense intracellular nucleic acids from pathogens such as bacteria and viruses, which leads to the induction of type I interferon (IFN) responses that are essential for an effective immune response. Further, these PRR pathways can be aberrantly activated by self DNA, which leads to autoimmunity. Therefore, understanding the signaling mechanisms that underlie PRR-induced production of IFN is vital to health and disease. ⋯ STING (stimulator of interferon genes) is a master regulator for the cyto-solic nucleic acid-mediated activation of IRF3 through TBK1 stimulation, but how the STING-TBK1-IRF3 signaling axis operates has been unclear. A study now shows that in response to cytosolic double-stranded DNA, the C-terminal tail of STING provides a scaffold to assemble IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3. Thus, STING directs TBK1 to activate IRF3 in DNA-sensing pathways.