TIM-1 Ubiquitination Mediates Dengue Virus Entry

• Main Authors: Ophélie Dejarnac, Mohamed Lamine Hafirassou, Maxime Chazal, Margaux Versapuech, Julien Gaillard, Manuel Perera-Lecoin, Claudia Umana-Diaz, Lucie Bonnet-Madin, Xavier Carnec, Jean-Yves Tinevez, Constance Delaugerre, Olivier Schwartz, Philippe Roingeard, Nolwenn Jouvenet, Clarisse Berlioz-Torrent, Laurent Meertens, Ali Amara
• Format: Article
• Language: English
• Published: Elsevier 2018-05-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718305424

Summary: 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. : Dejarnac et al. find that the phosphatidylserine receptor TIM-1 is a bona fide DENV receptor that mediates virus uptake through the clathrin-mediated pathway. TIM-1 is ubiquitinated at two lysines in its cytoplasmic tail and interacts with STAM-1 for efficient DENV infection.