INSERM U944-CNRS 7212, Laboratoire de Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie, Université Paris Diderot Sorbonne Paris Cité, Hôpital St. Louis, 75475 Paris Cedex 10, France.
Viral Genomics and Vaccination Unit, UMR-3569 CNRS, Pasteur Institute, 75724 Paris, France.
Cell Rep. 2018 May 8;23(6):1779-1793. doi: 10.1016/j.celrep.2018.04.013.
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.
登革热病毒（DENV）是一种主要的人类病原体，每年导致数百万人感染。尽管进行了深入的研究，但尚未鉴定出直接参与病毒内化的 DENV 受体。在这里，我们报告称，磷脂酰丝氨酸受体 TIM-1 是一种真正的 DENV 进入受体，在病毒内吞作用中发挥积极作用。TIM-1 的遗传缺失强烈削弱了 DENV 的感染。活感染细胞的全内反射荧光显微镜分析表明，TIM-1 主要局限于网格蛋白包被的陷窝中，并在病毒进入时与 DENV 一起被内吞。TIM-1 的细胞质结构域中有两个赖氨酸残基发生泛素化，该修饰对于 DENV 的内吞作用是必需的。此外，STAM-1 是参与泛素化货物细胞内运输的 ESCRT-0 复合物的一个组成部分，与 TIM-1 相互作用并对 DENV 感染是必需的。总的来说，我们的结果表明 TIM-1 是第一个被鉴定为 DENV 的真正受体。
