Human astrovirus coat protein binds C1q and MBL and inhibits the classical and lectin pathways of complement activation
Human astrovirus coat protein binds C1q and MBL and inhibits the classical and lectin pathways of complement activation
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DOI：
10.1016/j.molimm.2009.10.006
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发表时间：
2010-01-01
影响因子：
3.6
通讯作者：
Krishna, Neel K.
中科院分区：
文献类型：
--
作者：
Hair, Pamela S.;Gronemus, Jenny Q.;Krishna, Neel K.
人星状病毒（HAstV）构成引起婴儿胃肠炎的无包膜RNA病毒家族。我们以前已经证明，纯化的HAstV外壳蛋白（Cl？），其多个拷贝组成病毒衣壳，结合C1 q，导致经典补体途径活性的抑制。本研究的目的是进一步分析CP抑制C I激活的机制。CP抑制C1激活，防止裂解的C1 s的存在下，热聚集的IgG，一个强大的经典途径激活剂，其活性形式。CP还抑制强效过敏毒素C5 a的产生。CP与C1 q、分离的球状头部和C1 q分子的胶原样区域呈剂量依赖性结合。当CP加入到C1中时，C1 s从C1 q解离，表明CP在功能上取代了蛋白酶四聚体（C1 s-C1 r-C1 r-C1 s）。鉴于C1 q和MBL的结构和功能相关性，我们随后研究了CP和MBL之间的相互作用CP结合到纯化的MBL，并能够抑制甘露聚糖介导的凝集素途径的激活。有趣的是，CP不结合MBL的变体，该变体取代了与MASP-2（C1的功能同源物）结合的关键赖氨酸残基（Lys 55）。最后，CP被证明可以跨越物种屏障，抑制大鼠血清中C3的激活和MAC的形成。这些发现表明CP通过干扰识别分子与其同源丝氨酸蛋白酶的正常相互作用的新机制来抑制C1和MBL的激活。(C)2010爱思唯尔有限公司保留所有权利。
Human astroviruses (HAstVs) constitute a family of non-enveloped, RNA viruses which cause infantile gastroenteritis. We have previously demonstrated that purified HAstV coat protein (Cl?), multiple copies of which compose the viral capsid, bind C1q resulting in inhibition of classical complement pathway activity. The objective of this study was to further analyze the mechanism by which CP inhibits C I activation. CP inhibited C1 activation, preventing cleavage of C1s to its active form in the presence of heat-aggregated IgG, a potent classical pathway activator. CP also inhibited generation of the potent anaphylatoxin C5a. CP dose-dependently bound to C1q, the isolated globular heads and the collagen-like regions of the C1q molecule. When CP was added to C1, C1s dissociated from C1q suggesting that CP functionally displaces the protease tetramer (C1s-C1r-C1r-C1s). Given the structural and functional relatedness of C1q and MBL, we subsequently investigated the interactions between CP and MBL CP bound to purified MBL and was able to inhibit mannan-mediated activation of the lectin pathway. Interestingly, CP did not bind to a variant of MBL that replaces a lysine residue (Lys55) critical for binding to MASP-2, a functional homolog of C1s. Finally, CP was shown to cross the species barrier to inhibit C3 activation and MAC formation in rat serum. These findings suggest CP inhibits C1 and MBL activation via a novel mechanism of interference with the normal interaction of the recognition molecule with its cognate serine proteases. (C) 2010 Elsevier Ltd. All rights reserved.