Kesmir Can, van Noort Vera, de Boer Rob J, Hogeweg Paulien
Theoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Immunogenetics. 2003 Oct;55(7):437-49. doi: 10.1007/s00251-003-0585-6. Epub 2003 Aug 30.
Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon, the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.
细胞内蛋白质主要由蛋白酶体降解。在用γ干扰素刺激的细胞中，活性蛋白酶体亚基被形成免疫蛋白酶体的“免疫”亚基所取代。对免疫亚基的系统发育分析表明，它们的进化速度比其组成型对应物更快。这表明免疫蛋白酶体已经进化出一种与组成型蛋白酶体不同的功能。越来越多的实验降解数据确实表明，免疫蛋白酶体和组成型蛋白酶体的特异性不同。然而，两种形式的蛋白酶体的特异性差异究竟有多大尚未得到量化。仍然缺乏直接证据的主要问题是，免疫蛋白酶体是否产生更多的主要组织相容性复合体（MHC）配体。在这里，我们使用生物信息学工具来量化这些差异，并表明免疫蛋白酶体是一种比组成型蛋白酶体更具特异性的酶。此外，我们预测病原体蛋白质组的降解情况，发现免疫蛋白酶体产生的肽比组成型蛋白酶体产生的肽更适合作为MHC结合的配体。因此，我们的分析提供了证据，表明免疫蛋白酶体与主要组织相容性复合体共同进化，以优化脊椎动物细胞中的抗原呈递。
