Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism
Identification and Characterization of the First Cathelicidin from Sea Snakes with Potent Antimicrobial and Anti-inflammatory Activity and Special Mechanism
复制标题
第一个具有强效抗菌和抗炎活性的海蛇抗菌素的鉴定和表征及其特殊机制
DOI：
10.1074/jbc.m115.642645
复制
发表时间：
2015-07-03
影响因子：
4.8
通讯作者：
Wang, Yipeng
中科院分区：
文献类型：
--
作者：
Wei, Lin;Gao, Jiuxiang;Wang, Yipeng
Cathelicidins是一个基因编码的肽效应子家族，仅在脊椎动物中发现。它们在宿主抵抗微生物入侵的免疫防御中起关键作用。已经从几种脊椎动物中鉴定出几十种cathelicidin。然而，之前尚未对来自海洋爬行动物的凯萨林菌素进行过表征。在这里，我们报告了一个新的cathelicidin（HC-CATH）的鉴定和表征从海蛇Hydrophis cyanocinctus。Hc-CATH由30个氨基酸组成，序列为KFFKRLLKSVRRAVKKFRKKPRLIGLSTLL。圆二色谱和结构模型分析表明，Hc-CATH主要采取两亲性的α-螺旋构象在细菌膜模拟溶液。具有广谱、快速的抗菌活性。同时，它是高度稳定的，并显示出对哺乳动物细胞的低细胞毒性。Hc-CATH的微生物杀灭活性通过破坏细胞膜和裂解细菌细胞来实现。此外，Hc-CATH通过抑制LPS诱导的一氧化氮（NO）和促炎细胞因子（如TNF-α、IL-1 β和IL-6）的产生，表现出有效的抗炎活性。Hc-CATH直接与LPS结合以中和其毒性，并且它还与Toll样受体4（TLR 4/MD 2复合物）结合，从而抑制LPS与TLR 4/MD 2复合物的结合以及随后LPS诱导的炎症反应途径的激活。综上所述，我们的研究表明，Hc-CATH，第一个从海蛇中发现的具有抗菌和抗炎活性的cathelicidin，是开发肽抗生素的有力候选者。
Cathelicidins are a family of gene-encoded peptide effectors of innate immunity found exclusively in vertebrates. They play pivotal roles in host immune defense against microbial invasions. Dozens of cathelicidins have been identified from several vertebrate species. However, no cathelicidin from marine reptiles has been characterized previously. Here we report the identification and characterization of a novel cathelicidin (Hc-CATH) from the sea snake Hydrophis cyanocinctus. Hc-CATH is composed of 30 amino acids, and the sequence is KFFKRLLKSVRRAVKKFRKKPRLIGLSTLL. Circular dichroism spectroscopy and structure modeling analysis indicated that Hc-CATH mainly assumes an amphipathic alpha-helical conformation in bacterial membrane-mimetic solutions. It possesses potent broad-spectrum and rapid antimicrobial activity. Meanwhile, it is highly stable and shows low cytotoxicity toward mammalian cells. The microbial killing activity of Hc-CATH is executed through the disruption of cell membrane and lysis of bacterial cells. In addition, Hc-CATH exhibited potent anti-inflammatory activity by inhibiting the LPS-induced production of nitric oxide (NO) and pro-inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6. Hc-CATH directly binds with LPS to neutralize its toxicity, and it also binds to Toll-like receptor 4 (TLR4/MD2 complex), which therefore inhibits the binding of LPS to TLR4/MD2 complex and the subsequent activation of LPS-induced inflammatory response pathways. Taken together, our study demonstrates that Hc-CATH, the first cathelicidin from sea snake discovered to have both antimicrobial and anti-inflammatory activity, is a potent candidate for the development of peptide antibiotics.