TIM-1 Ubiquitination Mediates Dengue Virus Entry
TIM-1 Ubiquitination Mediates Dengue Virus Entry
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DOI：
10.1016/j.celrep.2018.04.013
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发表时间：
2018-05-08
期刊：
影响因子：
8.8
通讯作者：
Amara, Ali
中科院分区：
文献类型：
--
作者：
Dejarnac, Ophelie;Hafirassou, Mohamed Lamine;Amara, Ali
登革病毒（DENV）是一种主要的人类病原体，每年造成数百万人感染。尽管深入研究，但直接参与病毒内化的DENV受体尚未被表征。在这里，我们报告说，磷脂酰丝氨酸受体TIM-1是一个真正的登革病毒进入受体，在病毒内吞作用中发挥积极作用。TIM-1的基因切除强烈削弱了DENV感染。活感染细胞的全内反射荧光显微镜分析显示，TIM-1主要局限于网格蛋白包被的凹坑中，并且在病毒进入期间与DENV共内化。TIM-1在其胞质结构域的两个赖氨酸残基处被泛素化，并且这种修饰是DENV内吞作用所需的。此外，STAM-1是参与泛素化货物细胞内运输的ESCRT-0复合物的组分，与TIM-1相互作用，并且是DENV感染所需的。总的来说，我们的结果表明，TIM-1是第一个真正的DENV受体。
Dengue virus (DENV) is a major human pathogen causing millions of infections yearly. Despite intensive investigations, a DENV receptor that directly participates in virus internalization has not yet been characterized. Here, we report that the phosphatidylserine receptor TIM-1 is an authentic DENV entry receptor that plays an active role in virus endocytosis. Genetic ablation of TIM-1 strongly impaired DENV infection. Total internal reflection fluorescence microscopy analyses of live infected cells show that TIM-1 is mostly confined in clathrin-coated pits and is co-internalized with DENV during viral entry. TIM-1 is ubiquitinated at two lysine residues of its cytoplasmic domain, and this modification is required for DENV endocytosis. Furthermore, STAM-1, a component of the ESCRT-0 complex involved in intracellular trafficking of ubiquitinated cargos, interacts with TIM-1 and is required for DENV infection. Overall, our results show that TIM-1 is the first bona fide receptor identified for DENV.