Rhesus monkey rhadinovirus uses eph family receptors for entry into B cells and endothelial cells but not fibroblasts.
Rhesus monkey rhadinovirus uses eph family receptors for entry into B cells and endothelial cells but not fibroblasts.
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DOI：
10.1371/journal.ppat.1003360
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Desrosiers RC
中科院分区：
文献类型：
--
作者：
Hahn AS;Desrosiers RC
研究发现，细胞内肝配蛋白受体酪氨酸激酶（Ephrin receptor，Ephs）与恒河猴Rhadinovirus（RRV）的gH/gL糖蛋白复合物有效地相互作用。由于EphA 2最近被鉴定为卡波西肉瘤相关疱疹病毒（KSHV）的受体（Hahn等人，Nature Medicine 2012），我们平行分析了RRV和KSHV的Eh结合和Eh依赖性进入。14种Eph蛋白中有10种（包括A型和B型）与RRV gH/gL相互作用。两个RRV株具有显着不同的gH/gL序列表现出类似的，但略有不同的结合模式，以Ephs。KSHV的gH/gL显示出对EphA 2的高亲和力，但基本上较弱地结合到A型的仅少数其它Ephs。RRV 26-95进入B细胞和内皮细胞的生产性进入基本上完全依赖于Eph，因为来自重组病毒的GFP报告盒的表达可以被使用这些细胞的可溶性Eph诱饵阻断至大于95%。相反，根据这些相同的标准，RRV进入成纤维细胞和上皮细胞不依赖于Ephs。即使是高浓度和混合物的可溶性Eph诱饵不能减少任何明显的程度上的成纤维细胞和上皮细胞的数量，有效地进入RRV。因此，RRV在利用Eph家族受体有效进入B细胞和内皮细胞方面与其近亲KSHV相似。然而，RRV使用单独的、不同的、Eph非依赖性途径来生产性地进入成纤维细胞和上皮细胞。KSHV是否在某些情况下或在某种程度上也使用Eph非依赖性途径仍有待确定。在这里，我们表明，恒河猴rhadinovirus的gH/gL糖蛋白复合物结合，并介导病毒进入靶细胞通过细胞肝配蛋白受体酪氨酸激酶蛋白。恒河猴鼻状病毒是一种γ-2疱疹病毒，是人类卡波西肉瘤相关疱疹病毒（KSHV; HHV-8）的同源物。虽然KSHV主要或专门使用EphA 2进入，但RRV能够使用更广泛的A型和B型Eph受体。尽管两种RRV毒株类型之间以及RRV和KSHV之间的gH/gL存在大量序列变异，但使用Eph蛋白作为受体是保守的。重要的是，虽然根据各种标准，RRV进入B细胞和内皮细胞完全依赖于Eph受体，但根据这些相同的标准，RRV进入成纤维细胞和上皮细胞基本上不依赖于Eph受体。因此，RRV使用单独的、不同的、Eh非依赖性途径来生产性地进入成纤维细胞和上皮细胞。KSHV是否在某些情况下或在某种程度上也使用Eph非依赖性途径仍有待确定。
Cellular Ephrin receptor tyrosine kinases (Ephrin receptors, Ephs) were found to interact efficiently with the gH/gL glycoprotein complex of the rhesus monkey rhadinovirus (RRV). Since EphA2 was recently identified as a receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV) (Hahn et al., Nature Medicine 2012), we analyzed RRV and KSHV in parallel with respect to Eph-binding and Eph-dependent entry. Ten of the 14 Eph proteins, including both A- and B-type, interacted with RRV gH/gL. Two RRV strains with markedly different gH/gL sequences exhibited similar but slightly different binding patterns to Ephs. gH/gL of KSHV displayed high affinity towards EphA2 but substantially weaker binding to only a few other Ephs of the A-type. Productive entry of RRV 26-95 into B cells and into endothelial cells was essentially completely dependent upon Ephs since expression of a GFP reporter cassette from recombinant virus could be blocked to greater than 95% by soluble Eph decoys using these cells. In contrast, entry of RRV into fibroblasts and epithelial cells was independent of Ephs by these same criteria. Even high concentrations and mixtures of soluble Eph decoys were not able to reduce by any appreciable extent the number of fibroblasts and epithelial cells productively entered by RRV. Thus, RRV is similar to its close relative KSHV in the use of Eph family receptors for productive entry into B cells and endothelial cells. However, RRV uses a separate, distinct, Eph-independent pathway for productive entry into fibroblasts and epithelial cells. Whether KSHV also uses an Eph-independent pathway in some circumstances or to some extent remains to be determined. Here we show that the gH/gL glycoprotein complex of rhesus monkey rhadinovirus binds to and mediates entry of virus into target cells via cellular Ephrin receptor tyrosine kinase proteins. Rhesus monkey rhadinovirus is a gamma-2 herpesvirus that is a close homolog of the human Kaposi's sarcoma-associated herpesvirus (KSHV; HHV-8). While KSHV uses EphA2 principally or exclusively for entry, RRV is able to use a broader range of both A-type and B-type Eph receptors. The use of Eph proteins as receptors is conserved despite substantial sequence variation in gH/gL between two RRV strain types and between RRV and KSHV. Importantly, while entry of RRV into B cells and endothelial cells was completely dependent on the Eph receptors by a variety of criteria, entry of RRV into fibroblasts and epithelial cells was essentially independent of Eph receptors by these same criteria. Thus, RRV uses a separate, distinct, Eph-independent pathway for productive entry into fibroblasts and epithelial cells. Whether KSHV also uses an Eph-independent pathway in some circumstances or to some extent remains to be determined.
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