Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation
Binding of Flavivirus Nonstructural Protein NS1 to C4b Binding Protein Modulates Complement Activation
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DOI：
10.4049/jimmunol.1100750
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发表时间：
2011-07-01
影响因子：
4.4
通讯作者：
Atkinson, John P.
中科院分区：
文献类型：
--
作者：
Avirutnan, Panisadee;Hauhart, Richard E.;Atkinson, John P.
补体系统在包括黄病毒在内的多种病原体的先天免疫反应中起着关键的保护作用。黄病毒非结构蛋白1(NS1)是一种分泌型非结构糖蛋白，高水平聚集在血浆中，表达于感染细胞表面，但不存在于病毒颗粒中。以前的工作已经确定了黄病毒NS1通过与C1s和C4形成复合体来促进C4到C4b的切割，从而限制补体激活的免疫逃避作用。在这项研究中，我们证明了第二种机制，也涉及C4及其活性片段C4b，通过NS1拮抗补体激活。登革热、西尼罗河或黄热病病毒NS1与C4b结合蛋白(C4BP)直接相关，C4BP是一种补体调节血浆蛋白，可减弱经典途径和凝集素途径。可溶性NS1可使C4BP在溶液中和质膜上失活。作图研究表明，C4BP上NS1的相互作用部位与C4b结合部位部分重叠。综上所述，这些研究进一步确定了NS1在降低补体激活和控制黄病毒感染中C4的功能能力方面的免疫逃避潜力。免疫学杂志，2011,187：424-433。
The complement system plays a pivotal protective role in the innate immune response to many pathogens including flaviviruses. Flavivirus nonstructural protein 1 (NS1) is a secreted nonstructural glycoprotein that accumulates in plasma to high levels and is displayed on the surface of infected cells but absent from viral particles. Previous work has defined an immune evasion role of flavivirus NS1 in limiting complement activation by forming a complex with C1s and C4 to promote cleavage of C4 to C4b. In this study, we demonstrate a second mechanism, also involving C4 and its active fragment C4b, by which NS1 antagonizes complement activation. Dengue, West Nile, or yellow fever virus NS1 directly associated with C4b binding protein (C4BP), a complement regulatory plasma protein that attenuates the classical and lectin pathways. Soluble NS1 recruited C4BP to inactivate C4b in solution and on the plasma membrane. Mapping studies revealed that the interaction sites of NS1 on C4BP partially overlap with the C4b binding sites. Together, these studies further define the immune evasion potential of NS1 in reducing the functional capacity of C4 in complement activation and control of flavivirus infection. The Journal of Immunology, 2011, 187: 424-433.