Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.
Platelet-derived growth factor-α receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer.
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DOI：
10.1038/nmicrobiol.2016.82
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发表时间：
2016-06-06
影响因子：
28.3
通讯作者：
Perez L
中科院分区：
文献类型：
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作者：
Kabanova A;Marcandalli J;Zhou T;Bianchi S;Baxa U;Tsybovsky Y;Lilleri D;Silacci-Fregni C;Foglierini M;Fernandez-Rodriguez BM;Druz A;Zhang B;Geiger R;Pagani M;Sallusto F;Kwong PD;Corti D;Lanzavecchia A;Perez L
人巨细胞病毒（HCMV）编码病毒包膜中发现的至少25种膜糖蛋白。虽然gB代表融合蛋白，但两种糖蛋白复合物控制病毒的嗜性：gHgLgO三聚体参与成纤维细胞的感染，而gHgLpUL128L五聚体是内皮细胞、上皮细胞和骨髓细胞感染所需的。两份报告表明gB与ErbB1和PDGFRα结合，但这些结果不能解释病毒的嗜性，最近受到质疑。在这里，我们提供了gHgLgO三聚体的19bp重建，并表明它通过gO亚基与PDGFRα以高亲和力结合，PDGFRα在成纤维细胞上表达，但在上皮细胞上不表达。我们还提供了证据表明，三聚体是必不可少的病毒进入所有类型的细胞。此外，我们确定了五聚体作为ErbB途径的触发器，这是感染上皮细胞所必需的。这些发现有助于解释HCMV的广泛嗜性，并表明PDGFRα和病毒gO亚基可被新型抗病毒疗法靶向。
Human cytomegalovirus (HCMV) encodes at least 25 membrane glycoproteins that are found in the viral envelope. While gB represents the fusion protein, two glycoprotein complexes control the tropism of the virus: the gHgLgO trimer is involved in the infection of fibroblasts, while the gHgLpUL128L pentamer is required for infection of endothelial, epithelial and myeloid cells. Two reports suggested that gB binds to ErbB1 and PDGFRα, however these results do not explain the tropism of the virus and were recently challenged. Here we provide a 19Å reconstruction for the gHgLgO trimer and show that it binds with high affinity through the gO subunit to PDGFRα, which is expressed on fibroblasts but not on epithelial cells. We also provide evidences that the trimer is essential for viral entry in all cell types. Furthermore, we identified the pentamer as a trigger for the ErbB pathway, which is essential for infection of epithelial cells. These findings help explain the broad tropism of HCMV and indicate that PDGFRα and the viral gO subunit could be targeted by novel anti-viral therapies.