TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine.
TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine.
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DOI：
10.1371/journal.ppat.1003232
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发表时间：
2013-03
期刊：
影响因子：
6.7
通讯作者：
Choe H
中科院分区：
文献类型：
--
作者：
Jemielity S;Wang JJ;Chan YK;Ahmed AA;Li W;Monahan S;Bu X;Farzan M;Freeman GJ;Umetsu DT;Dekruyff RH;Choe H
人T细胞免疫球蛋白和含有粘蛋白结构域的蛋白质（TIM 1、3和4）特异性结合磷脂酰丝氨酸（PS）。TIM 1被认为是甲型肝炎病毒和埃博拉病毒的细胞受体，也被认为是登革病毒的进入因子。在这里，我们表明，TIM1促进逆转录病毒和病毒样颗粒（VLP）的感染假型与一系列病毒的进入蛋白，特别是那些从丝状病毒，黄病毒，新世界沙粒病毒和甲病毒科。TIM1还强烈增强了来自相同家族的复制能力病毒的感染，包括登革热病毒、塔卡里贝病毒、辛德毕斯病毒和罗斯河病毒。TIM 1和假病毒或VLP之间的所有相互作用是PS介导的，如脂质体阻断和TIM 1诱变实验所示。此外，其他PS结合蛋白，如Axl和TIM 4，促进感染类似于TIM 1。最后，阻断巨噬细胞上的PS受体抑制了埃博拉病毒VLP的进入，这表明PS受体可以促进生理相关细胞的感染。值得注意的是，由拉沙热病毒、甲型流感病毒和SARS冠状病毒的进入蛋白介导的感染在很大程度上不受TIM 1表达的影响。总之，我们的数据表明，TIM1和相关的PS结合蛋白促进不同家族的包膜病毒的感染，因此可能是广谱抗病毒治疗的有用靶点。为了感染细胞，包膜病毒通常利用细胞受体，其介导与病毒进入蛋白的特异性、高亲和力相互作用，并为病毒进入过程中的后续步骤准备进入蛋白。病毒进入也通过附着因子增强。虽然比受体特异性低，但附着因子可以通过增加特异性靶细胞的感染效率来改变感染过程，从而改变病毒性疾病的严重程度。在这里，我们观察到TIM蛋白，一组促进吞噬凋亡细胞的蛋白质，可以显着增强许多病毒的进入，包括埃博拉病毒，西尼罗河病毒和登革热病毒，而它们对其他病毒的进入几乎没有影响。病毒不能使用TIM蛋白可能是由于存在丰富的高亲和力受体（拉沙热病毒），或者因为TIM蛋白将病毒粒子导向非生产性内化途径（SARS冠状病毒，甲型流感病毒）。从机制上讲，TIM蛋白似乎通过结合暴露在病毒和细胞膜上的磷脂酰丝氨酸残基与包膜病毒和凋亡细胞类似地相互作用。总之，我们的研究表明，TIM蛋白是附着因子，可以大大提高许多致病性病毒的感染效率。
Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and virus-like particles (VLPs) pseudotyped with a range of viral entry proteins, in particular those from the filovirus, flavivirus, New World arenavirus and alphavirus families. TIM1 also robustly enhanced the infection of replication-competent viruses from the same families, including dengue, Tacaribe, Sindbis and Ross River viruses. All interactions between TIM1 and pseudoviruses or VLPs were PS-mediated, as demonstrated with liposome blocking and TIM1 mutagenesis experiments. In addition, other PS-binding proteins, such as Axl and TIM4, promoted infection similarly to TIM1. Finally, the blocking of PS receptors on macrophages inhibited the entry of Ebola VLPs, suggesting that PS receptors can contribute to infection in physiologically relevant cells. Notably, infection mediated by the entry proteins of Lassa fever virus, influenza A virus and SARS coronavirus was largely unaffected by TIM1 expression. Taken together our data show that TIM1 and related PS-binding proteins promote infection of diverse families of enveloped viruses, and may therefore be useful targets for broad-spectrum antiviral therapies. To infect cells, enveloped viruses typically utilize cellular receptors, which mediate specific, high-affinity interactions with the viral entry protein and prime the entry protein for subsequent steps in the viral entry process. Viral entry is also enhanced by attachment factors. Although less specific than receptors, attachment factors can alter the course of infection and thus severity of viral disease by increasing the infection efficiency of specific target cells. Here we observed that TIM proteins, a group of proteins that promote phagocytosis of apoptotic cells, can dramatically enhance the entry of a number of viruses, including Ebola, West Nile and dengue viruses, whereas they have little effect on the entry of other viruses. The inability of a virus to use TIM proteins may be due to the presence of an abundant, high-affinity receptor (Lassa fever virus), or because the TIM proteins direct virions to a non-productive internalization pathway (SARS coronavirus, influenza A virus). Mechanistically, TIM proteins appear to interact with enveloped viruses and apoptotic cells similarly by binding phosphatidylserine residues exposed on the viral and cellular membranes. Collectively our studies show that TIM proteins are attachment factors that can substantially improve the infection efficiency of a number of pathogenic viruses.
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