39500 Gilman Dr., University of California at San Diego, La Jolla, CA 92093-0687, USA.
FASEB J. 2014 Mar;28(3):1280-93. doi: 10.1096/fj.13-241497. Epub 2013 Dec 5.
Siglecs are sialic acid-binding Ig-like lectins that recognize sialoglycans via amino-terminal V-set domains. CD33-related Siglecs (CD33rSiglecs) on innate immune cells recognize endogenous sialoglycans as "self-associated molecular patterns" (SAMPs), dampening immune responses via cytosolic immunoreceptor tyrosine-based inhibition motifs that recruit tyrosine phosphatases. However, sialic acid-expressing pathogens subvert this mechanism through molecular mimicry. Meanwhile, endogenous host SAMPs must continually evolve to evade other pathogens that exploit sialic acids as invasion targets. We hypothesized that these opposing selection forces have accelerated CD33rSiglec evolution. We address this by comparative analysis of major CD33rSiglec (Siglec-3, Siglec-5, and Siglec-9) orthologs in humans, chimpanzees, and baboons. Recombinant soluble molecules displaying ligand-binding domains show marked quantitative and qualitative interspecies differences in interactions with strains of the sialylated pathogen, group B Streptococcus, and with sialoglycans presented as gangliosides or in the form of sialoglycan microarrays, including variations such as N-glycolyl and O-acetyl groups. Primate Siglecs also show quantitative and qualitative intra- and interspecies variations in expression patterns on leukocytes, both in circulation and in tissues. Taken together our data explain why the CD33rSiglec-encoding gene cluster is undergoing rapid evolution via multiple mechanisms, driven by the need to maintain self-recognition by innate immune cells, while escaping 2 distinct mechanisms of pathogen subversion.
信号识别颗粒是一种通过氨基端 V 型结构域识别唾液酸糖蛋白的 Ig 样凝集素。固有免疫细胞上的 CD33 相关信号识别颗粒（CD33rSiglecs）通过细胞溶质免疫受体酪氨酸抑制基序识别内源性唾液酸化糖蛋白作为“自我相关分子模式”（SAMPs），从而抑制免疫反应，该基序招募酪氨酸磷酸酶。然而，表达唾液酸的病原体通过分子模拟来破坏这种机制。同时，内源性宿主的 SAMPs 必须不断进化以逃避利用唾液酸作为入侵靶点的其他病原体。我们假设这些相反的选择压力加速了 CD33rSiglec 的进化。我们通过对人类、黑猩猩和狒狒中的主要 CD33rSiglec（Siglec-3、Siglec-5 和 Siglec-9）直系同源物进行比较分析来解决这个问题。显示配体结合结构域的重组可溶性分子在与唾液酸化病原体 B 群链球菌的菌株以及作为神经节苷脂或以唾液酸糖蛋白微阵列形式存在的唾液酸化糖蛋白相互作用方面表现出显著的种间差异，包括 N-糖基化和 O-乙酰化等变化。灵长类 Siglecs 在白细胞上的表达模式也表现出定量和定性的种内和种间差异，无论是在循环中还是在组织中。总之，我们的数据解释了为什么 CD33rSiglec 编码基因簇通过多种机制快速进化，这些机制是由维持固有免疫细胞自我识别的需要驱动的，同时逃避了两种不同的病原体破坏机制。
