TIM-1 Ubiquitination Mediates Dengue Virus Entry

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

TIM-1 Ubiquitination Mediates Dengue Virus Entry

2018

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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