Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain
Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain
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DOI：
10.1073/pnas.0406821101
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发表时间：
2004-10-26
影响因子：
11.1
通讯作者：
Compton, T
中科院分区：
文献类型：
--
作者：
Feire, AL;Koss, H;Compton, T
人巨细胞病毒（HCMV）能够在免疫功能低下患者的几乎每个器官系统中表现出疾病。这种广泛的致病嗜性与病毒在体外感染所有测试的脊椎动物细胞类型的能力相关，这一特征使得受体鉴定极其困难。在病毒进入过程中，HCMV诱导细胞形态学变化和与细胞整合素接合一致的信号级联;然而，HCMV结构蛋白不具有广泛使用的RGD整合素结合基序。我们在HCMV包膜糖蛋白B中鉴定了一个整合素结合去整合素样结构域，该结构域是整个疱疹病毒科病毒进入和融合所需的蛋白质。通过使用功能阻断整联蛋白Ab、β 1整联蛋白敲除小鼠成纤维细胞和糖蛋白B去整联蛋白样肽，符合可接受的受体标准，所有这些都支持α 2 β 1、α 6 β 1和α V β 3整联蛋白作为HCMV进入受体和在进入途径渗透阶段起作用的信号介质的关键作用。引人注目的是，糖蛋白B去整合素样结构域在许多人和动物疱疹病毒中是保守的，这表明整合素可能支持进入这个医学上重要的病毒家族。
Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrinbinding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, beta1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for alpha2beta1, alpha6beta1, and alphaVbeta3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.