Semen Clusterin Is a Novel DC-SIGN Ligand

Abstract

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 Lex and Ley, which are both excellent DC-SIGN ligands. These motifs enable semen clusterin to bind DC-SIGN with very high affinity (Kd 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.

Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells

“…Interestingly, semen contain the DC-SIGN ligand Semen Clusterin, which has also been shown to limit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4 þ T cells [34]. Moreover, semen-derived clusterin, but not clusterin from serum, bind DC-SIGN supporting our finding that different body fluids can interact with certain cells that could lead to diverse protection against pathogens.…”

Regulatory Circuits Mediated by Lectin-Glycan Interactions in Autoimmunity and Cancer

“…However, interaction with fucose-containing ligands increases only IL-10 and favors disassembly of this complex (Gringhuis et al, 2009). Recently, a highly fucosylated form of clusterin, an enigmatic protein implicated in autoimmunity and cancer, has been identified as a soluble ligand for DC-SIGN, suggesting its potential role in tolerance induction (Sabatte et al, 2011). Likewise, engagement of Dectin-1 can signal DCs either to promote generation of Th17 cells through activation of p38 mitogen-activated protein kinase or to drive differentiation of IL-10-producing tolerogenic DCs via ERKdependent mechanisms (Dillon et al, 2006;Osorio and Reis e Sousa, 2011).…”

The Chaperone Activity of Clusterin is Dependent on Glycosylation and Redox Environment

“…The N-terminal 22 amino acids represent a hydrophobic signal sequence for segregation into the endoplasmic reticulum (ER), where the nascent polypeptide is processed to a 60 kDa high mannose single chain precursor (pre-secretory CLU, psCLU) possessing five intramolecular disulfide bonds [3,4,5]. After translocation to the Golgi-apparatus, psCLU is terminally glycosylated with the mass percentage rate of carbohydrates reaching up to 30%, depending on the tissue [6]. Upon transport to the cell surface, the precursor is cleaved by a furin-like proprotein convertase (PC) producing an N-terminal α-chain and a C-terminal β-chain [7].…”