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Glycodelin: A Lipocalin with Diverse Glycoform-Dependent Actions

,* , , , and .

* Corresponding Author: Department of Clinical Chemistry, University of Helsinki, Biomedicum Helsinki, 4th floor, Haartmaninkatu 8, 00029 HUS, Finland. Email: mseppala@welho.com

Introduction

Glycodelin has many names in the literature, such as placental protein 14 (PP14), human placental organ-specific α2-globulin, or progesterone-dependent endometrial protein, based on electrophoretic characteristics, regulation, or tissue of first identification. 1-4 After detailed information became available on its sites of synthesis, primary structure, complex-type oligosaccharide structures and biological actions, the protein was renamed as “glycodelin” to highlight significance of its unique oligosaccharide moieties for biological activity.5-7 Based on structural similarity with β-lactoglobulins8 containing a retinol-binding motif9 glycodelin is the major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation.10 Due to its unique oligosaccharide moieties affecting biological functions glycodelin serves as a model in studies on functional glycomics in a number of clinical areas.

Structure

Glycodelin Gene

In the Human Genome Organisation (HUGO), the official symbol for the glycodelin gene is PAEP (progestogen-associated endometrial protein).11 The glycodelin gene has been assigned to chromosome 9, band q34.12 This is the locus in which other lipocalin genes, such as α1-microglobulin/bikunin, prostaglandin D synthase and tear lipocalin 1 and 2 genes are also located.13-15 The glycodelin gene is 5.05 kb long and, like many lipocalin genes, it is divided into seven exons.16 The nucleotide sequence encoding the retinol-binding motif of β-lactoglobulins is conserved in the glycodelin gene. Four putative glucocorticoid/progesterone response elements (PRE) are found at positions -1799, -1071, -745, and -302 of the gene promoter, and two additional putative PREs are present at +1912 and +1965.10,16

Primary Structure

The first studies on N-terminal sequence of glycodelin uncovered 59% identity with horse β-lactoglobulin and 23% identity with human retinol-binding protein.8,17 The amino acid sequence of glycodelin is 180 residues long, including an 18 amino acid signal sequence.5 Highest similarity, 91%, is with rhesus macaque glycodelin (PP14) (NCBI BLASTP search on June 8th, 2005). In β-lactoglobulins, four cysteine residues at positions 66, 106, 119, and 160 are responsible for intramolecular disulfide bridges.18 All of them are conserved in glycodelin. But unlike β-lactoglobulins, glycodelin is a glycoprotein that contains 17.5% carbohydrate.2 Moreover, unlike β-lactoglobulin, glycodelin-A has not been found to bind retinoic acid or retinol.19

Carbohydrate Moieties

Glycodelin has three potential N-linked glycosylation sites at Asn 28, Asn 63 and Asn 85 (numbering according to mature protein without signal sequence).5 Two of them (Asn 28 and Asn 63) are glycosylated in uterine glycodelin-A and seminal plasma glycodelin-S, but in a different fashion.6,20 In glycodelin-A, the major nonreducing epitopes in the complextype glycans are Galβ1-4GlcNAc (lacNAc), GalNAcβ1-4GlcNAc (lacdiNAc), NeuAcα2-6Galβ1-4GlcNAc (sialylated lacNAc), NeuAcα2-6GalNAcβ1-4GlcNAc (sialylated lacdiNAc), Galβ1-4(Fucα1-3)GlcNAc (blood group Lewisx), and GalNAcβ1- (Fucβ1-3)GlcNAc (lacdiNAc analogue of Lewisx).6 Oligosaccharides bearing terminal sialylated lacNAc or lacdiNAc antennae may manifest immunosuppressive effects by blocking adhesive and activation-related events mediated by CD22, the human B cell receptor, and a biantennary N-linked fucosylated oligosaccharide bearing Lewisx has been reported to inhibit E-selectin mediated adhesion. Indeed, glycodelin has been found to inhibit E-selectin mediated cell adhesion.21 Purified glycodelin preparations isolated from amniotic fluid, endometrium, decidua and pregnancy serum are closely similar in respect of their physicochemical and immunological properties, allowing them to be categorized as glycodelin-A.22 Glycodelin-S is a human seminal plasma glycodelin isoform that is immunologically indistinguishable from uterine glycodelin-A, but unlike the latter, it does not inhibit human sperm-zona pellucida binding, and all of its glycans are different from those of glycodelin-A. Glycodelin-S contains no sialylated glycans, its glycans are unusually fucose-rich, and the major complex-type structures are biantennary glycans with Lewisx and Lewisy [Fucα1-2Galβ1-4 (Fucα1-3) GlcNAc] antennae.20 Glycodelin-F from follicular fluid also shares the protein core with glycodelin-A, but these two isoforms differ in glycosylation, as demonstrated by fluorophore-assisted carbohydrate electrophoresis and lectin binding characteristics.23

Folding

Differentially glycosylated glycodelin isoforms glycodelin-A and glycodelin-S share similar thermodynamic parameters of reversible denaturation. This suggests that native folding of these isoforms is not influenced by the differences in glycosylation.19 The Swiss-Model-deduced tertiary structure of glycodelin is similar to that of bovine β-lactoglobulin and other lipocalins. The glycans may form a clustered saccharide patch,24 in which the carbohydrates from more than one glycosylation site form a cluster. Because the folding patterns are similar in glycodelin-A and glycodelin-S they provide a model for studies on the effects of differential glycosylation on the conformational stability and function.

Tissues and Cells of Origin

Reproductive System

Many studies have shown that glycodelin-A is synthesized by glandular and luminal surface epithelium of the endometrium in response to progesterone exposure and secreted mainly to uterine fluid or amniotic fluid during pregnancy.10 In the ovary, another glycodelin isoform, glycodelin-F, is synthesized in luteinized granulosa cells25 and, in the fallopian tube, both glycodelin-A and -F are produced in the epithelial cells.26-29

Other Tissues

In normal breast tissue, glycodelin is synthesized in ductal and lobular epithelium.30 It has also been found in sweat glands.31 In the male reproductive tract, both glycodelin-S protein and mRNA are localized to glands of the seminal vesicle and ampullary part of the vas deferens.32 Glycodelin mRNA is constitutively expressed in the hematopoietic tissue of the bone marrow,33 notably in the megakaryocytic lineage.34 Glycodelin has also been found in malignant tumors (see below).

Regulation and Biological Actions

Sperm Capacitation

Glycodelin-S from seminal plasma does not inhibit sperm-egg binding in spite of the same protein core and immunoreactivity as in glycodelin-A.20 The biological role of glycodelin-S has been extensively elucidated by collaborative research between Hong Kong and Helsinki.29,35 Experiments on binding kinetics have demonstrated the presence of two binding sites for glycodelin-S on human spermatozoa. These binding sites are saturable, reversible, and bind to glycodelin-S in a time- and concentration- dependent manner. Differently glycosylated glycodelin isoforms -A and -F do not compete with glycodelin-S for these binding sites. Bovine serum albumin and cyclodextrin induce cholesterol efflux from human spermatozoa. Glycodelin-S significantly reduces the cholesterol efflux induced by either of these stimulators, and it exerts this effect upstream of protein kinase activation in the adenylyl cyclase/protein kinase A/tyrosine kinase signaling pathway in spermatozoa, resulting in suppression of capacitation. Deglycosylated glycodelin-S does not bind to sperm cells and has no effect on bovine serum albumin-induced capacitation. Again, these findings demonstrate the importance of carbohydrate moieties of glycodelin-S for the biological action of this molecule,35 particularly because the said processes are activated upon removal of glycodelin-S from the spermatozoa. In vivo, the dissociation probably takes place during passage of spermatozoa through the cervix, as suggested by in vitro experiments employing a cervical fluid surrogate.35 In view of these observations glycodelin-S appears to play a role in maintaining an uncapacitated state in the human spermatozoa before their passage through the cervix.

Acrosome Reaction

Glycodelin-F is secreted from luteinized ovarian granulosa cells into preovulatory follicular fluid25 and transferred with the cumulus cells into fallopian tube at ovulation. Like glycodelin-A, it binds on the sperm head. Binding kinetics studies using radiolabeled glycodelin-F have demonstrated two binding sites on human spermatozoa, and one of these binding sites also binds glycodelin-A. Thus, glycodelin-A displaces only 70% of the labeled glycodelin-F bound on human spermatozoa. Immunocytochemically glycodelin-F is localized to the acrosome region of the human spermatozoa, and sperm-bound glycodelin-F but not glycodelin-A inhibits progesterone-induced acrosome reaction and sperm-egg binding. Deglycosylation of glycodelin-F abolishes its binding to spermatozoa.36 Studies on neoglycoproteins have shown that the binding of glycodelin-A to spermatozoa involves mannose, fucose and possibly E-selectin residues, while that of glycodelin-F involves mannose, fucose and N-acetylglucosamine, but not the selectin residue.37 Before fertilization, during sperm passage through the cumulus/corona cell layer that surrounds the oocyte, glycodelin-F is removed from spermatozoa, and progesterone-induced acrosome reaction and sperm-egg binding capacity are restored.25 The uptake of glycodelin-F by the cumulus cells seems to be unique among proteins of the lipocalin family, as some other lipocalin proteins do not have the same effect. Again, glycosylation may explain the difference, as the cumulus cells may partially deglycosylate glycodelin-F.25 In view of these observations one of the biological actions of glycodelin-F appears to be in the prevention of premature acrosome reaction before the spermatozoa have penetrated through the cumulus oophorus matrix to bind to the zona pellucida.

Sperm Binding to the Zona Pellucida

Glycodelin-A was the first endogenous glycoprotein that was found to potently and dose-dependently inhibit binding of spermatozoa to the zona pellucida.38 The inhibition was caused by prior binding of glycodelin-A on the spermatozoa. In the uterus, synthesis of glycodelin-A is temporally regulated by progesterone. Thus, during the estrogen-dominated fertile window, absence of glycodelin-A synthesis in the endometrium is meaningful because of its anti-fertilization activity. This property of uterine glycodelin-A during the luteal phase of the cycle is glycosylation-dependent.20 Glycodelin-F has even stronger inhibitory activity on sperm-zona binding than glycodelin-A does.23 This activity is reduced during passage through the cumulus oophorus matrix of the glycodelin-F covered sperm.25 These diverse biological actions of unique isoforms make glycodelin a representative example for studies on functional glycomics during early events of the fertilization process (Table 1).

Table 1. Biological actions of glycodelin isoforms.

Table 1

Biological actions of glycodelin isoforms.

Immunosuppression, Implantation and Placentation

In addition to its anti-fertilization propensity glycodelin-A has immunosuppressive activities. These include inhibitory activity on lymphocyte proliferation,39 NK-cell cytotoxicity,40 T-cell proliferation and Th1-type cytokine response,41 and induction of T-cell apoptosis.42 The inhibition of T-cell activation is mediated by tyrosine phosphatase receptor CD45.43 Glycodelin binds to pregnancy zone protein and alpha(2)-macroglobulin, both potentiating glycodelin's immunosuppressive activity.44 Glycodelin also regulates B cell responses.45 A receptor for glycodelin has been found on human monocytes.46 While glycosylation is important for gamete interactions, the immunosuppressive properties of glycodelin are likely to be carbohydrate-independent, except in the case of apoptotic activity, where presence of sialic acid is important.47,48 While glycodelin-A binds on spermatozoa, it remains to be proven whether glycodelin-bound sperm would have decreased immunogenicity in the female body.

Given its inhibitory activity on natural killer cells and the T cells, uterine glycodelin-A likely plays a part in fetomaternal defense mechanisms during implantation and placentation, by counteracting maternal immune cell rejection of the fetal semiallograft.40,49 Implantation normally takes place eight days after the luteinizing hormone (LH) surge. At that time a full array of immune cells are present in the endometrium. Studies on global gene profiling have shown that, in a normal ovulatory cycle, glycodelin expression is significantly increased during the window of implantation.50 This is translated into increased glycodelin synthesis and secretion.10,51 Clinical observations on low glycodelin levels in uterine fluid and serum from patients with early pregnancy loss (EPL) are compatible with the role of glycodelin in placentation.52-54

Examples of Clinical Relevance

Controlled Ovarian Stimulation (COH)

There are many clinical situations in which glycodelin secretion may be altered because of changes in local endocrine microenvironment. COH employing ovarian suppression with gonadotropin-releasing hormone agonists in combination with controlled stimulation with follicle-stimulating hormone and LH is widely used in women undergoing in vitro fertilization. The treatment increases ovarian secretion of estrogen and androgen, and progesterone secretion may also be affected. Therefore, exogenous progesterone is commonly used to support the luteal phase. These changes are likely to affect hormone-regulated protein secretion from the endometrium in general, and glycodelin secretion in particular, interfering with endometrial receptivity. In vitro studies have shown that androgens decrease endometrial glycodelin secretion.55 In a prospective controlled study,56 endometrial biopsies from oocyte donors undergoing COH cycles were compared with biopsies from control women with natural cycles. Immunolocalization of glycodelin-A was demonstrated in endometrial glands and not in the endometrial stroma in all subjects throughout the implantation window. Higher and faster rise of endometrial glycodelin-A expression was noted in COH cycles compared to controls. A significant positive correlation was noted between glycodelin-A expression in the endometrium and serum estradiol levels in natural cycles, whereas neither LH nor progesterone was correlated with endometrial glycodelin-A expression. These results show that COH cycles have a significantly increased endometrial glycodelin-A expression throughout the implantation phase as compared with normal menstrual cycles and this may have an impact on implantation.

Failure of Implantation and Placentation

The polycystic ovary syndrome (PCOS) is associated with infertility and an increased rate of early pregnancy loss. This may reflect defects in ovulation, implantation and placentation. Hyperinsulinemia is an independent risk factor for EPL. Serum glycodelin correlates positively with insulin sensitivity index during weeks 3-5 of pregnancy.54 Comparing women with PCOS who experienced EPL with those who did not, serum glycodelin was significantly lower during weeks 3-5 of pregnancy.54 During the first trimester, both epithelial glycodelin and stromal IGFBP-1 serum concentrations are markedly decreased in PCOS, implicating endometrial epithelial and stromal dysfunction during the peri-implantation period and early pregnancy as a mechanism for EPL in PCOS. These changes may be secondary to reduced insulin sensitivity and hyperinsulinemia. Thus, glycodelin may serve as a biomarker for increased risk of early pregnancy loss due to deficient endometrial environment for maintenance of pregnancy. Interestingly, treatment with metformin, an insulin-lowering agent, increases serum glycodelin concentration in patients with PCOS, suggesting that insulin may regulate glycodelin secretion.57 However, a study employing euglycemic hyperinsulinemic clamp has shown no acute glycodelin-lowering effect of insulin, ruling out any direct glycodelin-reducing effects of insulin. 58 However, indirect long term effects mediated by insulin through stromal factors on epithelial glycodelin secretion cannot be excluded.

Contraception

The absence of glycodelin-A in ovulatory phase endometrium is biologically meaningful because glycodelin has anti-fertilization activity.38 But, glycodelin-A synthesis can be induced in endometrium over the fertile window. This can be achieved by sustained administration of progestagens, e.g., in the form of subdermal contraceptive implants or levonorgestrel hormone-releasing intrauterine system.59,60 In view of the anti-fertilization effect of glycodelin-A it is possible that induction of glycodelin secretion over the fertile window may contribute to the contraceptive mechanism of these methods. Interestingly, emergency contraception with levonorgestrel brings about changes in the secretory pattern of glycodelin-A, but only in those women who take the pills before the LH surge. Importantly, in these women the serum glycodelin level rises earlier during the fertile window and glycodelin expression in endometrium is weaker during the implantation window.61 As the great majority of human fertilizations follow from sexual intercourse during the six-day period ending in ovulation, i.e., at or before the LH surge, these results suggest that the early rise of glycodelin-A secretion may contribute to the mechanism(s) whereby pregnancy is prevented in emergency contraception.

Antiviral Contraception

Like bovine β-lactoglobulin,62 glycodelin-A can be chemically modified in such a way that it blocks the binding site on CD4 for the HIV surface glycoprotein, synthesis of viral gp 120, and infection of peripheral blood mononuclear cells by the primary HIV isolate THA/93/051, thus potentially inhibiting HIV transmission.63 Now that a cell line producing the contraceptive isoform has been identified by recombinant technology,64 these findings may have application for locally applied antiviral contraception.

Cancer

Glycodelin is a normal constituent of differentiated cells in the endometrium and certain other tissues. Therefore it is not frequently expressed in poorly differentiated malignant cells, whereas cancerous tissue containing both normal and malignant cells may contain glycodelin. Examples of such tumors are various histolopathological forms of breast cancer,30 ovarian serous carcinoma,65,66 and biphasic synovial sarcoma67 in which epithelial components express glycodelin. Experiments on glycodelin-negative carcinoma cell lines transfected with glycodelin cDNA have demonstrated increased epithelial differentiation after transfection with the sense strand but not with the antisense strand.31,68 Similar results have been obtained in coculture of carcinoma cells with normal stromal cells in the presence of basement membrane components.69 Both approaches have resulted in glycodelin expression in carcinoma cells, concomitantly with reduced cell proliferation and reversion of the malignant phenotype. These results demonstrate an active role of normal stromal cells, basement membrane components and glycodelin in epithelial differentiation and glandular morphogenesis. This disposition of glycodelin is significant in patients with certain carcinomas, such as ovarian serous carcinoma in which glycodelin-expressing tumors carry better prognosis than glycodelin-negative tumors of the same clinical stage and histological grade66 (Table 2). Indeed, glycodelin appears to have fundamental inhibitory effects on certain anti-apoptotic survival genes involved in tumor cell growth.68

Table 2. Glycodelin—areas of potential clinical interest.

Table 2

Glycodelin—areas of potential clinical interest.

Summary

Glycodelin is a glycosylated lipocalin whose biological actions fall into the category of functional glycomics, i.e., a glycoprotein with the same protein core has different biological actions depending on its specific glycosylation pattern. These diverse effects of glycodelin are best known in the reproductive system (Fig. 1). Glycodelin-A synthesis in secretory endometrium and glycodelin-F synthesis in luteinized granulosa cells and the oviduct are temporally related to the action of progesterone in the female, whereas no hormonal association is known for the glycodelin-S synthesis in male seminal vesicles. These various glycodelin isoforms regulate such functions as sperm capacitation, acrosome reaction, and binding of spermatozoa to the zona pellucida of the oocyte during early events of fertilization. Examples of the mode of action and clinical relevance of these findings are provided. Unlike many other lipocalins, glycodelin does not bind retinoic acid or retinol, and experiments on its carrier functions have given negative results so far. Glycodelin has immunosuppressive activity, in part independently of glycosylation. Given that the embryo is a semiallograft in the mother, the immunosuppressive nature and abundance of glycodelin at the implantation site may have an impact on fetomaternal defence mechanisms, supported by clinical observations. Being a normal constituent of well-differentiated reproductive tissues glycodelin is rarely expressed in cancer. But where present, its expression in carcinoma tissue is associated with better prognosis. Experiments on the induction of glycodelin synthesis have demonstrated reduced proliferation and reversion of the malignant phenotype in glycodelin-expressing carcinoma cell lines. These results indicate that glycodelin has morphogen-like characteristics.

Figure 1. Biological roles of glycodelin.

Figure 1

Biological roles of glycodelin. Sperm-egg binding: Glycodelin isoforms from amniotic and follicular fluids (glycodelin-A and glycodelin-F, respectively) inhibit sperm-egg binding in hemizona assay. The hemizonae with tightly bound spermatozoa, shown as (more...)

Acknowledgements

Original work in this review was supported by the Academy of Finland, the University of Helsinki, the Federation of the Finnish Life and Pension Insurance Companies, and the Cancer Foundation of Finland.

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