Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.
Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.
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Pigeon 的新型 Cathelicidins 强调了 Avain Cathelicidins 的进化趋同性及其调节先天免疫的功能。
DOI：
10.1038/srep11082
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发表时间：
2015-07-21
影响因子：
4.6
通讯作者：
Wang Y
中科院分区：
文献类型：
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作者：
Yu H;Lu Y;Qiao X;Wei L;Fu T;Cai S;Wang C;Liu X;Zhong S;Wang Y
天青素是一种短阳离子宿主防御肽，在宿主天然免疫系统中发挥着重要作用。在这里，我们鉴定了两个新的长春花素，氯-CATH2和3，从豆科植物中分离得到。通过系统进化树和Ka/Ks计算分析，支持CATH2向CATH1和3进化的正向选择，它们起源于共同的祖先，可能属于一个超家族。CL-CATH2和3均采用圆二色谱鉴定的两亲性α-螺旋构象和Rosetta建立的三维结构。在鸟类中表达丰度最高的CATH2家族的CL-CATH2具有相对较弱的抗菌活性，但却作用于天然免疫反应，没有表现出不良的毒性。在脂多糖刺激的巨噬细胞中，ClCATH2通过MAPK和NF-κB信号通路，显著下调诱导型一氧化氮合酶和促炎细胞因子的基因和蛋白表达，同时增强抗炎细胞因子。分子对接首次表明，长春花碱与Toll样受体4-MD-2复合体的髓系分化因子2(MD-2)结合到内毒素结合口袋的开放区域，进而抑制TLR4通路。因此，我们的结果为中草药阻断TLR4信号的机制提供了新的见解。
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.