文昌鱼新型Ig模式识别受体CDP的功能研究

The origin of the adaptive immune rearrangement receptor BCR/TCR is a classic puzzle of immunology and evolutionary biology. There is a hypothesis that BCR/TCR may come from the original Ig pattern recognition receptors which acquired rearrangement mechanism. Recently, RAG transposon, the precursor of the rearrangement enzyme, was found in amphioxus, indicating that the origin of antibody rearrangement can be traced back to invertebrate. At present, the function of pathogenic pattern recognition receptors based on the classic Ig architecture has not been studied clearly in invertebrates. Therefore, the search of such molecules in invertebrates helps to further understand the origin of BCR/TCR. We found lots of Ig superfamily members in amphioxus, including VCP, VCBP and CDP similar to BCR/TCR. The extracellular region of CDP has an IgV-IgC(-IgC) structure, and the intracellular region has a Death domain. The extracellular region of CDP is polymorphic, which can bind different bacteria. Then, CDP transduce these extracellular signals to the intracellular through its Death domain, and finally initiates the immune response. The functional mechanism of CDP is like BCR and Toll like receptor. This project intends to make a thorough study of these novel Ig receptors to provide new clues for revealing the structure and function origin of BCR/TCR.

适应性免疫重排受体BCR/TCR的起源是免疫学和进化生物学的经典谜题。有假说认为BCR/TCR可能来自获得了重排机制的原始Ig模式识别受体。最近，人们在文昌鱼中发现了重排激活酶的前身RAG转座子，表明抗体重排的起源可追溯到无脊椎动物。但是，目前人们还没有在无脊椎动物中发现功能确切、基于经典Ig架构的病原模式识别受体。因此，在无脊椎动物中寻找这类分子，有助进一步认识BCR/TCR的起源。我们在文昌鱼中发现了大量的Ig超家族分子，包括VCP、VCBP和CDP等三类与BCR/TCR类似的新型Ig样分子。其中，CDP的胞外区具有IgV-IgC(-IgC)架构，胞内区具有Death结构域。其胞外区具有多态性，可结合不同细菌，并通过Death将信号传递到胞内，启动免疫反应，作用机制像是BCR和Toll样受体的结合体。本项目拟对这些新型Ig受体作深入研究，为揭示BCR/TCR的结构与功能起源提供新线索。

文昌鱼基因组中拥有大量的IgSF分子，包括许多具有新颖蛋白结构域组合的分子，这些分子中可能潜藏着脊椎动物适应性免疫起源与演化的线索。本项目对文昌鱼新型Ig受体分子CDP的功能做了深入研究，描绘了CDP细胞内传递机制，筛选到了其胞外结构所识别的细菌糖链组分。对CDP分子机制的研究以及类似具有经典Ig架构的分子的挖掘，将有助于揭示BCR/TCR的结构与功能起源。此外，对文昌鱼IRAK分子的进一步研究发现，不同物种中IRAK家族分子在信号通路中所处的位置相对保守，但其功能确有较大差异，这使得相关信号通路在与病原体的对抗演化中既具有保守性又具有可塑性。