Immunology Research Centre, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Sci Signal. 2012 Mar 6;5(214):pe9. doi: 10.1126/scisignal.2002919.
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. A key transcription factor that is involved in these pathways is IFN regulatory factor 3 (IRF3), which is often activated by the kinase TANK-binding kinase 1 (TBK1). 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.
细胞质模式识别受体（PRRs）可识别来自细菌和病毒等病原体的细胞内核酸，从而诱导 I 型干扰素（IFN）反应，这对于有效的免疫反应至关重要。此外，这些 PRR 途径可被自身 DNA 异常激活，从而导致自身免疫。因此，了解 PRR 诱导 IFN 产生的信号转导机制对于健康和疾病至关重要。参与这些途径的一个关键转录因子是干扰素调节因子 3（IRF3），它通常由激酶 TANK 结合激酶 1（TBK1）激活。STING（干扰素基因刺激物）是通过 TBK1 刺激使细胞质核酸介导的 IRF3 激活的主调节剂，但 STING-TBK1-IRF3 信号轴如何运作尚不清楚。一项研究表明，在对细胞质双链 DNA 的反应中，STING 的 C 端尾巴提供了一个支架来组装 IRF3 和 TBK1，从而导致 TBK1 依赖的 IRF3 磷酸化。因此，STING 指导 TBK1 在 DNA 感应途径中激活 IRF3。
