Sheedy Frederick J, O'Neill Luke A J
School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.
J Leukoc Biol. 2007 Aug;82(2):196-203. doi: 10.1189/jlb.1206750. Epub 2007 Apr 20.
Signaling by two of the most important bacteria-sensing TLRs, TLR2 and TLR4, involves two adaptor proteins, MyD88 adaptor-like (Mal) and Toll/IL-1 receptor (TIR) domain-containing adaptor-inducing IFN-beta (Trif)-related adaptor molecule (TRAM). Recently, new insights into the functioning of these two adapters have emerged. Mal is required by both TLRs to act as a bridge to recruit the adaptor MyD88, leading ultimately to NF-kappaB activation. Similarly, TRAM acts as a bridge to recruit TRIF to the TLR4 complex, leading to activation of the transcription factor IFN regulatory factor 3. Consistent with Mal and TRAM being key points of control, recent evidence suggests that they are subject to regulation by phosphorylation. Further, a variant in Mal in humans has been found to protect against multiple infectious diseases. Finally, another TIR domain-containing adaptor, sterile alpha and HEAT/armadillo motif protein (SARM), has been shown to act as an inhibitor of TRIF-dependent signaling. These recent discoveries add to the complexity of TLR signaling and highlight specific control mechanisms for TLR2 and TLR4 signaling.
两种最重要的细菌感应Toll样受体（TLR），即TLR2和TLR4，其信号传导涉及两种衔接蛋白，即MyD88衔接蛋白样分子（Mal）和含Toll/白细胞介素-1受体（TIR）结构域的衔接蛋白诱导干扰素-β（Trif）相关衔接分子（TRAM）。最近，对于这两种衔接蛋白的功能有了新的认识。两种TLR都需要Mal作为桥梁来招募衔接蛋白MyD88，最终导致核因子-κB激活。同样，TRAM作为桥梁将TRIF招募到TLR4复合物，导致转录因子干扰素调节因子3的激活。与Mal和TRAM作为控制关键点一致，最近的证据表明它们受到磷酸化调节。此外，已发现人类中Mal的一个变体可预防多种传染病。最后，另一种含TIR结构域的衔接蛋白，即无菌α和HEAT/犰狳基序蛋白（SARM），已被证明可作为TRIF依赖性信号传导的抑制剂。这些最新发现增加了TLR信号传导的复杂性，并突出了TLR2和TLR4信号传导的特定控制机制。
