TIM-1 Ubiquitination Mediates Dengue Virus Entry
2018
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
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.
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