title: Differential Use of the C-Type Lectins L-SIGN and DC-SIGN for Phlebovirus Endocytosis.
abstract: Bunyaviruses represent a growing threat to humans and livestock globally. The receptors, cellular factors and endocytic pathways used by these emerging pathogens to infect cells remain largely unidentified and poorly characterized. DC-SIGN is a C-type lectin highly expressed on dermal dendritic cells that has been found to act as an authentic entry receptor for many phleboviruses (Bunyaviridae), including Rift Valley fever virus (RVFV), Toscana virus (TOSV) and Uukuniemi virus (UUKV). We found that these phleboviruses can exploit another C-type lectin, L-SIGN, for infection. L-SIGN shares 77% sequence homology with DC-SIGN and is expressed on liver sinusoidal endothelial cells. L-SIGN is required for UUKV binding but not for virus internalization. An endocytosis-defective mutant of L-SIGN was still able to mediate virus uptake and infection, indicating that L-SIGN acts as an attachment receptor for phleboviruses rather than an endocytic receptor. Our results point out a fundamental difference in the use of the C-type lectins L-SIGN and DC-SIGN by UUKV to enter cells, although both proteins are closely related in terms of molecular structure and biological function. This study sheds new light on the molecular mechanisms by which phleboviruses target the liver and also highlights the added complexity in virus-receptor interactions beyond attachment.
authors.affiliation: CellNetworks - Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Psylvia
authors.initials: P
authors.lastname: Léger
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Canada.|Current address: Inserm UMR_S1134, Paris, France.
authors.forename: Marilou
authors.initials: M
authors.lastname: Tetard
authors.affiliation: CellNetworks - Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.|INRS-Institut Armand-Frappier, Laval, Canada.|Reproduction Genetics Unit, Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital, Heidelberg, Germany.
authors.forename: Berthe
authors.initials: B
authors.lastname: Youness
authors.affiliation: CellNetworks - Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cordes
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Canada.|UR_0892 Unité de Virologie et Immunologie Moléculaire, INRA, CRJ, Jouy-en-Josas, France.
authors.forename: Ronan N
authors.initials: RN
authors.lastname: Rouxel
authors.affiliation: Structural Virology, Institut Pasteur, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Flamand
authors.affiliation: CellNetworks - Cluster of Excellence and Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.|INRS-Institut Armand-Frappier, Laval, Canada.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Lozach
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000821:virology; D016856:Phlebovirus / Q000472:pathogenicity / Q000502:physiology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human
keywords: C-type lectins; CD209; CD209L; DC-SIGN; DC-SIGNR; L-SIGN; Rift Valley fever virus; Uukuniemi virus; binding; bunyavirus; endocytic motif; endocytosis; phlebovirus; uptake; virus receptor