Yang R B, Mark M R, Gurney A L, Godowski P J
Department of Molecular Biology, Genentech, Inc., San Francisco, CA 94080, USA.
J Immunol. 1999 Jul 15;163(2):639-43.
Human Toll-like receptor 2 (TLR2) is a signaling receptor that responds to LPS and activates NF-kappaB. Here, we investigate further the events triggered by TLR2 in response to LPS. We show that TLR2 associates with the high-affinity LPS binding protein membrane CD14 to serve as an LPS receptor complex, and that LPS treatment enhances the oligomerization of TLR2. Concomitant with receptor oligomerization, the IL-1R-associated kinase (IRAK) is recruited to the TLR2 complex. Intracellular deletion variants of TLR2 lacking C-terminal 13 or 141 aa fail to recruit IRAK, which is consistent with the inability of these mutants to transmit LPS cellular signaling. Moreover, both deletion mutants could still form complexes with wild-type TLR2 and act in a dominant-negative (DN) fashion to block TLR2-mediated signal transduction. DN constructs of myeloid differentiation protein, IRAK, TNF receptor-associated factor 6, and NF-kappaB-inducing kinase, when coexpressed with TLR2, abrogate TLR2-mediated NF-kappaB activation. These results reveal a conserved signaling pathway for TLR2 and IL-1Rs and suggest a molecular mechanism for the inhibition of TLR2 by DN variants.
人类Toll样受体2（TLR2）是一种信号受体，可对脂多糖（LPS）作出反应并激活核因子κB（NF-κB）。在此，我们进一步研究TLR2在响应LPS时触发的事件。我们发现TLR2与高亲和力LPS结合蛋白膜CD14结合，形成LPS受体复合物，并且LPS处理可增强TLR2的寡聚化。与受体寡聚化同时发生的是，白细胞介素-1受体相关激酶（IRAK）被招募到TLR2复合物中。缺乏C末端13或141个氨基酸的TLR2细胞内缺失变体无法招募IRAK，这与这些突变体无法传递LPS细胞信号的情况一致。此外，这两种缺失突变体仍可与野生型TLR2形成复合物，并以显性负性（DN）方式发挥作用，阻断TLR2介导的信号转导。当与TLR2共表达时，髓样分化蛋白、IRAK、肿瘤坏死因子受体相关因子6和NF-κB诱导激酶的DN构建体可消除TLR2介导的NF-κB激活。这些结果揭示了TLR2和白细胞介素-1受体的保守信号通路，并提示了DN变体抑制TLR2的分子机制。
