Role of the Phosphatidylserine Receptor TIM-1 in Enveloped-Virus Entry
Role of the Phosphatidylserine Receptor TIM-1 in Enveloped-Virus Entry
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DOI：
10.1128/jvi.01025-13
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发表时间：
2013-08-01
影响因子：
5.4
通讯作者：
Maury, Wendy
中科院分区：
文献类型：
--
作者：
Moller-Tank, Sven;Kondratowicz, Andrew S.;Maury, Wendy
细胞表面受体T细胞免疫球蛋白粘蛋白结构域1（TIM-1）显著增强丝状病毒对上皮细胞的感染。在这里，我们表明TIM-1 IgV结构域的关键磷脂酰丝氨酸（PtdSer）结合残基对于埃博拉病毒（EBOV）通过与病毒包膜上的PtdSer直接相互作用进入至关重要。PtdSer脂质体而非磷脂酰胆碱脂质体与TIM-1竞争EBOV假病毒体结合和转导。此外，膜联蛋白V（AnxV）取代TIM-1 IgV结构域，支持PtdSer依赖性机制。我们的研究结果表明，TIM-1依赖性摄取EBOV发生的凋亡模拟。此外，TIM-1增强了多种包膜病毒的感染，包括甲病毒和杆状病毒。作为与病毒粒子相关的PtdSer在TIM-1介导的摄取中的关键作用的进一步证据，TIM-1增强了缺乏糖蛋白的假病毒粒子和病毒样蛋白（VLP）的内化，提供了TIM-1和PtdSer结合受体可以不依赖于糖蛋白介导病毒摄取的证据。这些结果为TIM-1作为介导病毒摄取的PtdSer结合受体的广泛作用提供了证据。PtdSer结合受体的利用可以解释这些病毒的广泛嗜性，并为控制其毒力提供新的途径。
The cell surface receptor T cell immunoglobulin mucin domain 1 (TIM-1) dramatically enhances filovirus infection of epithelial cells. Here, we showed that key phosphatidylserine (PtdSer) binding residues of the TIM-1 IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PtdSer on the viral envelope. PtdSer liposomes but not phosphatidylcholine liposomes competed with TIM-1 for EBOV pseudovirion binding and transduction. Further, annexin V (AnxV) substituted for the TIM-1 IgV domain, supporting a PtdSer-dependent mechanism. Our findings suggest that TIM-1-dependent uptake of EBOV occurs by apoptotic mimicry. Additionally, TIM-1 enhanced infection of a wide range of enveloped viruses, including alphaviruses and a baculovirus. As further evidence of the critical role of enveloped-virion-associated PtdSer in TIM-1-mediated uptake, TIM-1 enhanced internalization of pseudovirions and virus-like proteins (VLPs) lacking a glycoprotein, providing evidence that TIM-1 and PtdSer-binding receptors can mediate virus uptake independent of a glycoprotein. These results provide evidence for a broad role of TIM-1 as a PtdSer-binding receptor that mediates enveloped-virus uptake. Utilization of PtdSer-binding receptors may explain the wide tropism of many of these viruses and provide new avenues for controlling their virulence.