Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1
Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1
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DOI：
10.1038/nsmb.2367
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发表时间：
2012-09-01
影响因子：
16.8
通讯作者：
Savvides, Sawas N.
中科院分区：
文献类型：
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作者：
Elegheert, Jonathan;Bracke, Nathalie;Savvides, Sawas N.
造血人集落刺激因子1 （hCSF-1）是对抗病毒和微生物感染和癌症的先天和适应性免疫所必需的。人类病原体爱泼斯坦-巴尔病毒分泌裂解周期蛋白BARF1，该蛋白中和hCSF-1以实现免疫调节。在这里，我们发现BARF1以皮摩尔亲和力结合hCSF-1的二聚体界面，远离同源受体结合位点，在BARF1环状体的外围建立了一个具有三个hCSF-1的长寿命复合物。BARF1将二聚体hCSF-1锁定为非活性构象，使其无法通过其在人类单核细胞上的同源受体发出信号。这揭示了hCSF-1协同作用在信号传导中的新功能作用。我们提出了一种新的病毒策略范式，其特征是竞争型的变构诱饵受体，它结合宿主生长因子的有效隔离和失活来消除同源信号复合物的合作组装。
Hematopoietic human colony-stimulating factor 1 (hCSF-1) is essential for innate and adaptive immunity against viral and microbial infections and cancer. The human pathogen Epstein-Barr virus secretes the lytic-cycle protein BARF1 that neutralizes hCSF-1 to achieve immunomodulation. Here we show that BARF1 binds the dimer interface of hCSF-1 with picomolar affinity, away from the cognate receptor binding site, to establish a long-lived complex featuring three hCSF-1 at the periphery of the BARF1 toroid. BARF1 locks dimeric hCSF-1 into an inactive conformation, rendering it unable to signal via its cognate receptor on human monocytes. This reveals a new functional role for hCSF-1 cooperativity in signaling. We propose a new viral strategy paradigm featuring an allosteric decoy receptor of the competitive type, which couples efficient sequestration and inactivation of the host growth factor to abrogate cooperative assembly of the cognate signaling complex.