Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, 342011, Rajasthan, India.
Fish Shellfish Immunol. 2019 Oct;93:17-27. doi: 10.1016/j.fsi.2019.07.034. Epub 2019 Jul 13.
Chemokines are chemotactic proteins involved in host defense through the migration of immune-regulatory cells to the site of infection. Interleukin-8 (CXCL8/IL8) is the most studied "ELR-CXC chemokine/neutrophil activating chemokine (NAC) that regulate neutrophil trafficking during infections and inflammation by binding to its cognate G-protein coupled receptors CXCR1/CXCR2. The "ELR" motif of NAC chemokines is essential for the CXCR1/CXCR2 receptor activation. In order to understand the evolutionary origin of "ELR" motif in the CXC chemokines, a thorough evolutionary study of CXCL8 gene from various fishes and primates was performed. Phylogenetic analysis revealed that the CXCL8 gene can be classified into four distinct lineages (CXCL8-L1a, CXCL8-L1b, CXCL8-L2, and CXCL8-L3), where CXCL8-L1a is the fastest evolving lineage and CXCL8-L3 is the slowest. Selection analysis suggested that The "ELR/DLR" motif containing branches (gadoid and coelacanth) are positively selected. The probable evolutionary trend of "ELR" motif suggested that this motif in ancestor CXCL8 is evolved from the GGR of Lamprey (Agnatha), followed by duplication giving rise to two main motifs in CXCL8 "NXH" in L3 lineage and "ELR/DLR" in L1a/L1b lineages. Although, structural analysis suggested that the overall topology of the CXCL8 proteins is similar, differences do exist at the individual structural elements among the members of different lineages. Functional distance analysis suggested that the CXCL8-L3 lineage is more distant compared to the CXCL8-L1a and L1b lineages from the inferred ancestor. Functional divergence analysis between different lineages suggested that most of the selected residues are important for receptor or glycosaminoglycan binding. Such a functional diversification can be attributed to the novel set of functions adopted by CXCL8 in various species.
趋化因子是一类参与宿主防御的趋化蛋白，通过免疫调节细胞向感染部位迁移来实现。白细胞介素-8 (CXCL8/IL8) 是研究最广泛的“ELR-CXC 趋化因子/中性粒细胞激活趋化因子 (NAC)”，通过与同源 G 蛋白偶联受体 CXCR1/CXCR2 结合来调节中性粒细胞在感染和炎症期间的迁移。NAC 趋化因子的“ELR”基序对于 CXCR1/CXCR2 受体的激活至关重要。为了了解 CXC 趋化因子中“ELR”基序的进化起源，我们对来自各种鱼类和灵长类动物的 CXCL8 基因进行了全面的进化研究。系统发育分析表明，CXCL8 基因可分为四个不同的谱系 (CXCL8-L1a、CXCL8-L1b、CXCL8-L2 和 CXCL8-L3)，其中 CXCL8-L1a 是进化最快的谱系，而 CXCL8-L3 是进化最慢的谱系。选择分析表明，包含“ELR/DLR”基序的分支（鳕形目和腔棘鱼）受到正选择。“ELR”基序的可能进化趋势表明，该基序在祖先 CXCL8 中是从七鳃鳗 (无颌类) 的 GGR 进化而来的，随后通过复制产生了 CXCL8 中的两个主要基序，L3 谱系中的“NXH”和 L1a/L1b 谱系中的“ELR/DLR”。尽管结构分析表明 CXCL8 蛋白的整体拓扑结构相似，但不同谱系成员之间的个别结构元素存在差异。功能距离分析表明，与 CXCL8-L1a 和 L1b 谱系相比，CXCL8-L3 谱系与推断的祖先更为遥远。不同谱系之间的功能分化分析表明，大多数选择的残基对于受体或糖胺聚糖结合很重要。这种功能多样化可以归因于 CXCL8 在各种物种中采用的一套新的功能。
