Origination of new immunological functions in the costimulatory molecule B7-H3: the role of exon duplication in evolution of the immune system.
Origination of new immunological functions in the costimulatory molecule B7-H3: the role of exon duplication in evolution of the immune system.
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共刺激分子 B7-H3 中新免疫功能的起源：外显子重复在免疫系统进化中的作用
DOI：
10.1371/journal.pone.0024751
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Sun J;Fu F;Gu W;Yan R;Zhang G;Shen Z;Zhou Y;Wang H;Shen B;Zhang X
B7- h3是最近发现的B7家族成员，在人和小鼠中具有不同的亚型。小鼠B7-H3基因只有一个异构体（2IgB7-H3），具有两个igg样结构域，而人类B7-H3基因有两个异构体（2IgB7-H3和4IgB7-H3）。本研究通过对硬骨鱼和哺乳动物的系统基因组调查发现，在猪、豚鼠、牛、狗、非洲象、熊猫、巨兽和高等灵长类动物中也存在4IgB7-H3异构体，这是由串联外显子重复引起的。进一步的序列分析表明，这种重复在第一个IgC结构域产生了一个新的保守区域，可能使4IgB7-H3不能释放可溶性形式，而2IgB7-H3同时具有膜和可溶性形式。通过三维（3D）结构建模和融合蛋白结合分析，我们发现复制的异构体具有不同的结构，并且可能与活化T细胞上的另一个潜在受体结合。在T细胞增殖实验中，人2IgB7-H3 （h2IgB7-H3）和小鼠B7-H3 （mB7-H3）均增加了T细胞增殖和IL-2、IFN-γ的产生，而人4IgB7-H3 （h4IgB7-H3）与对照组相比，减少了细胞因子的产生和T细胞增殖。此外，h2IgB7-H3和mB7-H3在体外均上调脂多糖（LPS）激活单核细胞的功能。综上所述，我们的数据表明，在脊椎动物的进化过程中，B7-H3外显子复制在许多哺乳动物物种中促成了新的4IgB7-H3异构体的产生，这些异构体在免疫应答中发挥了不同的功能。
B7-H3, a recently identified B7 family member, has different isoforms in human and mouse. Mouse B7-H3 gene has only one isoform (2IgB7-H3) with two Ig-like domains, whereas human B7-H3 has two isoforms (2IgB7-H3 and 4IgB7-H3). In this study a systematic genomic survey across various species from teleost fishes to mammals revealed that 4IgB7-H3 isoform also appeared in pigs, guinea pigs, cows, dogs, African elephants, pandas, megabats and higher primate animals, which resulted from tandem exon duplication. Further sequence analysis indicated that this duplication generated a new conserved region in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membrane and soluble forms. Through three-dimensional (3D) structure modeling and fusion-protein binding assays, we discovered that the duplicated isoform had a different structure and might bind to another potential receptor on activated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3) and mouse B7-H3 (mB7-H3) both increased T cell proliferation and IL-2, IFN-γ production, whereas human 4IgB7-H3 (h4IgB7-H3) reduced cytokine production and T cell proliferation compared to control. Furthermore, both h2IgB7-H3 and mB7-H3 upregulated the function of lipopolysacharide (LPS)-activated monocyte in vitro. Taken together, our data implied that during the evolution of vertebrates, B7-H3 exon duplication contributed to the generation of a new 4IgB7-H3 isoform in many mammalian species, which have carried out distinct functions in the immune responses.
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