Häcker Hans, Redecke Vanessa, Blagoev Blagoy, Kratchmarova Irina, Hsu Li-Chung, Wang Gang G, Kamps Mark P, Raz Eyal, Wagner Hermann, Häcker Georg, Mann Matthias, Karin Michael
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Nature. 2006 Jan 12;439(7073):204-7. doi: 10.1038/nature04369. Epub 2005 Nov 23.
Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains, but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response.
Toll样受体（TLRs）被病原体相关分子模式激活，以诱导先天性免疫反应并产生促炎细胞因子、干扰素和抗炎细胞因子。TLRs通过含有Toll/白细胞介素-1受体（TIR）结构域的接头激活下游效应器，但TLR效应器功能多样化的机制尚不清楚。为了从生化角度剖析TLR信号传导，我们建立了一个用于分离由二聚化接头组装的信号复合物的系统。以髓样分化因子88（MyD88）作为典型接头，我们鉴定出肿瘤坏死因子受体相关因子3（TRAF3）是TIR信号复合物的一个新组分，它与TRAF6一起被招募。利用来自TRAF3和TRAF6缺陷小鼠的髓样细胞，我们发现TRAF3对于I型干扰素（IFN）和抗炎细胞因子白细胞介素-10（IL-10）的诱导至关重要，但对于促炎细胞因子的表达是可有可无的。事实上，由于IL-10产生缺陷，TRAF3缺陷细胞会过度产生促炎细胞因子。尽管TRAF3和TRAF6在结构上相似，但它们的功能在很大程度上是不同的。TRAF3也被招募到接头TICAM-1（含Toll/IL-1受体结构域的接头诱导IFN-β），并且是将蛋白激酶TBK1（也称为NAK）召集到TIR信号复合物中所必需的，从而解释了它在IFN反应激活中的独特作用。
