Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Cell. 2014 Feb 13;156(4):705-16. doi: 10.1016/j.cell.2014.01.019.
The Toll-like receptors (TLRs) of the innate immune system are unusual in that individual family members are located on different organelles, yet most activate a common signaling pathway important for host defense. It remains unclear how this common signaling pathway can be activated from multiple subcellular locations. Here, we report that, in response to natural activators of innate immunity, the sorting adaptor TIRAP regulates TLR signaling from the plasma membrane and endosomes. TLR signaling from both locations triggers the TIRAP-dependent assembly of the myddosome, a protein complex that controls proinflammatory cytokine expression. The actions of TIRAP depend on the promiscuity of its phosphoinositide-binding domain. Different lipid targets of this domain direct TIRAP to different organelles, allowing it to survey multiple compartments for the presence of activated TLRs. These data establish how promiscuity, rather than specificity, can be a beneficial means of diversifying the subcellular sites of innate immune signal transduction.
先天免疫系统中的 Toll 样受体（TLRs）不同寻常，因为其家族成员位于不同的细胞器上，但大多数都激活了一条对宿主防御很重要的共同信号通路。目前尚不清楚这条共同的信号通路如何能从多个亚细胞位置被激活。在这里，我们报告说，在对天然的先天免疫激活剂的反应中，衔接蛋白 TIRAP 调节来自质膜和内体的 TLR 信号转导。来自这两个位置的 TLR 信号触发了 MyD88 依赖性衔接蛋白复合物（myddosome）的组装，该复合物控制促炎细胞因子的表达。TIRAP 的作用取决于其磷酸肌醇结合域的混杂性。该结构域的不同脂质靶标将 TIRAP 引导至不同的细胞器，使其能够在多个隔室中检测到激活的 TLR。这些数据确立了混杂性，而不是特异性，如何成为多样化先天免疫信号转导亚细胞位点的有益手段。
