Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV).
Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV).
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Plxdc家族成员是恒河猴横纹肌病毒（RRV）的新型受体。
DOI：
10.1371/journal.ppat.1008979
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Hahn AS
中科院分区：
文献类型：
--
作者：
Großkopf AK;Schlagowski S;Fricke T;Ensser A;Desrosiers RC;Hahn AS
恒河猴杆状病毒(RRV)是恒河猴的γ2型疱疹病毒，与人类致病的卡波西肉瘤相关疱疹病毒(KSHV)有许多生物学特征。这两种病毒，以及关系更远的爱泼斯坦-巴尔病毒，都与受体酪氨酸激酶(Ephs)家族的细胞受体结合。然而，Eph相互作用对RRV进入的重要性因细胞类型的不同而不同，这表明存在Eph非依赖性进入途径。因此，我们的目标是通过亲和富集法和质谱法鉴定更多的RRV细胞受体。我们鉴定了一个额外的受体家族，含有网状结构域的蛋白1和2(Plxdc1/2)，它结合了RRV Gh/gl糖蛋白复合体。RRV与可溶性Plxdc2诱骗受体预先孵育可减少约60%的感染，而Plxdc1和2的过表达显著增加RRV的易感性和其他边缘允许的Raji细胞的细胞-细胞融合。而Plxdc2与RRV 26-95和17577株之间的相互作用是保守的，而Plxdc1与RRV 26-95Gh特异地相互作用。这种相互作用是由RRV Gh N端的一个短基序介导的，该基序在分离物26-95和分离物17577之间部分保守，而在KSHV Gh中不存在。该基序的突变取消了与Plxdc1/2的相互作用，并以一种细胞类型特异性的方式减少了RRV的感染。综上所述，我们的发现表明Plxdc1/2是RRV的新的相互作用伙伴和进入受体，并支持伽马疱疹病毒Gh/gl复合体的N-末端结构域是一个多功能受体结合域的概念。此外，Plxdc1/2的使用定义了KSHV和RRV之间的一个重要的生物学差异。KSHV是一组恶性肿瘤的病原体，这些恶性肿瘤造成了很大的疾病负担，特别是在撒哈拉以南非洲。RRV是恒河猴的一种相关病毒，已显示出作为KSHV的模型系统和开发免疫策略的前景。为了充分发挥RRV动物模型系统的潜力，详细了解KSHV和RRV之间的共性和差异是关键。在这里，我们描述了包含网络结构域的蛋白1和2作为一个新的受体家族，它介导RRV的进入，而不是KSHV的进入。使用缺失Plxdc相互作用基序的RRV突变体进行的感染实验表明，Plxdc受体对RRV感染具有细胞类型特异性贡献。由于有关Plxdc1/2及其生物学功能的信息仍然很少，分析RRV-Plxdc的相互作用将有助于表征该受体家族的生理和病理生理作用。
The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by ~60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility and cell-cell fusion of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26–95 and 17577, Plxdc1 specifically interacts with RRV 26–95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26–95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 and reduced RRV infection in a cell type-specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV. KSHV is the causative agent of a group of malignancies which account for a substantial disease burden in particular in sub-Saharan Africa. RRV, a related virus of rhesus macaques, has shown promise as model system for KSHV and for the development of immunization strategies. To exploit the full potential of the RRV animal model system, detailed knowledge of commonalities and differences between KSHV and RRV is key. Here, we describe the Plexin domain containing proteins 1 and 2 as a novel receptor family which mediates entry of RRV, but not of KSHV. Infection experiments using RRV mutants deleted of the Plxdc interaction motif suggest a cell type-specific contribution of Plxdc receptors to RRV infection. As information on Plxdc1/2 and its biological function is still sparse, analysis of the RRV–Plxdc interaction will help to characterize the physiological and pathophysiological role of this receptor family.
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影响因子：
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作者：
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