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
Mohamed Lamine Hafirassou
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
Maxime Chazal
Viral Genomics and Vaccination Unit, UMR-3569 CNRS, Pasteur Institute, 75724 Paris, France
Margaux Versapuech
Laboratoire Interaction Hôte-Virus, Institut Cochin, INSERM U1016-CNRS UMR8104-Université Paris Descartes, 75014 Paris, France
Julien Gaillard
INSERM U966 MAVIVH, Faculté de Médecine, Université de Tours, Tours, France
Manuel Perera-Lecoin
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
Claudia Umana-Diaz
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
Lucie Bonnet-Madin
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
Xavier Carnec
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
Jean-Yves Tinevez
Institut Pasteur, Citech, UTechS PBI, 75724 Paris Cedex 15, France
Constance Delaugerre
Departement des Maladies Infectieuses, Hôpital Saint Louis, 75010 Paris, France
Olivier Schwartz
Unité Virus et Immunité, Institut Pasteur, 75724 Paris, France
Philippe Roingeard
INSERM U966 MAVIVH, Faculté de Médecine, Université de Tours, Tours, France
Nolwenn Jouvenet
Viral Genomics and Vaccination Unit, UMR-3569 CNRS, Pasteur Institute, 75724 Paris, France
Clarisse Berlioz-Torrent
Laboratoire Interaction Hôte-Virus, Institut Cochin, INSERM U1016-CNRS UMR8104-Université Paris Descartes, 75014 Paris, France
Laurent Meertens
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; Corresponding author
Ali Amara
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; Corresponding author
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.
