Semen clusterin is a novel DC-SIGN ligand.
The C-type lectin receptor dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is an important player in the recognition of pathogens by dendritic cells. A plethora of pathogens including viruses, bacteria, parasites, and fungi are recognized by DC-SIGN through both mannose and fucose-containing glycans expressed on the pathogen surface. In this study, we identified semen clusterin as a novel DC-SIGN ligand. Semen clusterin, but not serum clusterin, expresses an extreme abundance of fucose-containing blood-type Ags such as Le(x) and Le(y), which are both excellent DC-SIGN ligands. These motifs enable semen clusterin to bind DC-SIGN with very high affinity (K(d) 76 nM) and abrogate the binding of HIV-1 to DC-SIGN. Depletion of clusterin from semen samples, however, did not completely prevent the ability of semen to inhibit the capture of HIV-1 by DC-SIGN, supporting that besides clusterin, semen contains other DC-SIGN ligands. Further studies are needed to characterize these ligands and define their contribution to the DC-SIGN-blocking activity mediated by semen. Clusterin is an enigmatic protein involved in a variety of physiologic and pathologic processes including inflammation, atherosclerosis, and cancer. Our results uncover an unexpected heterogeneity in the glycosylation pattern of clusterin and suggest that the expression of high concentrations of fucose-containing glycans enables semen clusterin to display a unique set of biological functions that might affect the early course of sexually transmitted infectious diseases.
INSERM U653, Immunité et Cancer, Institut Curie Paris, Paris 75248, France.
Juan
J
Sabatte
Wolfgang
W
Faigle
Ana
A
Ceballos
Willy
W
Morelle
Christian
C
Rodríguez Rodrígues
Federico
F
Remes Lenicov
Michel
M
Thépaut
Franck
F
Fieschi
Emilio
E
Malchiodi
Marisa
M
Fernández
Fernando
F
Arenzana-Seisdedos
Hugues
H
Lortat-Jacob
Jean-Claude
JC
Michalski
Jorge
J
Geffner
Sebastian
S
Amigorena
D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood / Q000378:metabolism*; D051152:Clusterin / Q000097:blood / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D005643:Fucose / Q000378:metabolism; D006031:Glycosylation; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000097:blood / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008358:Mannose / Q000378:metabolism; D008875:Middle Aged; D011485:Protein Binding / Q000276:immunology; D011956:Receptors, Cell Surface / Q000097:blood / Q000378:metabolism*; D011994:Recombinant Proteins / Q000097:blood / Q000378:metabolism; D012661:Semen / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000998:Antiviral Agents; D015815:Cell Adhesion Molecules; D051152:Clusterin; D005643:Fucose; D037181:Lectins, C-Type; D008024:Ligands; D008358:Mannose; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin