Molecular mechanisms for viral mimicry of a human cytokine: Activation of gp130 by HHV-8 interleukin-6
Molecular mechanisms for viral mimicry of a human cytokine: Activation of gp130 by HHV-8 interleukin-6
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DOI：
10.1016/j.jmb.2003.10.070
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发表时间：
2004-01-09
影响因子：
5.6
通讯作者：
Garcia, KC
中科院分区：
文献类型：
--
作者：
Boulanger, MJ;Chow, DC;Garcia, KC
卡波西肉瘤相关疱疹病毒（KSHV，或HHV 8）编码人类白细胞介素-6 （IL-6）的致病性病毒同源物。与人IL-6 （ML-6）不同，病毒IL-6 （vIL-6）直接结合并激活共享的人细胞因子信号受体gp130，而不需要与特定的a受体预络合。在这里，我们剖析了il -6模仿hIL-6的生化和功能基础。我们发现，除了“与α受体无关”的四聚体vIL-6/gp130复合体外，病毒细胞因子还可以与人α受体（il - 6rα）结合形成六聚体vIL-6/ 1l - 6rα /gp130复合体，其信号效力增强。与il -6六聚体的组装序列相反，预先形成的il -6/gp130四聚体可以事后以il -6依赖的方式被IL-6Ralpha修饰。病毒和人类细胞因子/gp130界面的详细比较表明，vIL-6已经进化出一种独特的分子策略来与gp130相互作用，其受体结合位点的结构组成几乎完全不同。病毒IL-6似乎巧妙地结合了趋同和出人意料的分化两种分子策略，使gp130寡聚，并激活与人类相似的下游信号级联反应。(C) 2003 Elsevier Ltd.版权所有。
Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV 8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (ML-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific a-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "alpha-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human alpha-receptor (IL-6Ralpha) to form a hexameric vIL-6/1L-6Ralpha/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Ralpha, post facto, in a vIL-6-dependent fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart. (C) 2003 Elsevier Ltd. All rights reserved.