Pregnancy-specific glycoproteins: evolution, expression, functions and disease associations

in Reproduction
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Tom Moore School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

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John M Williams School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

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Maria Angeles Becerra-Rodriguez School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

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Matthew Dunne Institute of Food Nutrition and Health, ETH Zurich, Zurich, Switzerland

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Robert Kammerer Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald – Insel Riems, Germany

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Gabriela Dveksler Uniformed Services University of the Heath Sciences, Bethesda, Maryland, USA

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Correspondence should be addressed to T Moore or G Dveksler; Email: t.moore@ucc.ie or gabriela.dveksler@usuhs.edu
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Pregnancy-specific glycoproteins (PSGs) are members of the immunoglobulin superfamily and are closely related to the predominantly membrane-bound CEACAM proteins. PSGs are produced by placental trophoblasts and secreted into the maternal bloodstream at high levels where they may regulate maternal immune and vascular functions through receptor binding and modulation of cytokine and chemokine expression and activity. PSGs may have autocrine and paracrine functions in the placental bed, and PSGs can activate soluble and extracellular matrix bound TGF-β, with potentially diverse effects on multiple cell types. PSGs are also found at high levels in the maternal circulation, at least in human, where they may have endocrine functions. In a non-reproductive context, PSGs are expressed in the gastrointestinal tract and their deregulation may be associated with colorectal cancer and other diseases. Like many placental hormones, PSGs are encoded by multigene families and they have an unusual phylogenetic distribution, being found predominantly in species with hemochorial placentation, with the notable exception of the horse in which PSG-like proteins are expressed in the endometrial cups of the epitheliochorial placenta. The evolution and expansion of PSG gene families appear to be a highly active process, with significant changes in gene numbers and protein domain structures in different mammalian lineages and reports of extensive copy number variation at the human locus. Against this apparent diversification, the available evidence indicates extensive conservation of PSG functions in multiple species. These observations are consistent with maternal–fetal conflict underpinning the evolution of PSGs.

Abstract

Pregnancy-specific glycoproteins (PSGs) are members of the immunoglobulin superfamily and are closely related to the predominantly membrane-bound CEACAM proteins. PSGs are produced by placental trophoblasts and secreted into the maternal bloodstream at high levels where they may regulate maternal immune and vascular functions through receptor binding and modulation of cytokine and chemokine expression and activity. PSGs may have autocrine and paracrine functions in the placental bed, and PSGs can activate soluble and extracellular matrix bound TGF-β, with potentially diverse effects on multiple cell types. PSGs are also found at high levels in the maternal circulation, at least in human, where they may have endocrine functions. In a non-reproductive context, PSGs are expressed in the gastrointestinal tract and their deregulation may be associated with colorectal cancer and other diseases. Like many placental hormones, PSGs are encoded by multigene families and they have an unusual phylogenetic distribution, being found predominantly in species with hemochorial placentation, with the notable exception of the horse in which PSG-like proteins are expressed in the endometrial cups of the epitheliochorial placenta. The evolution and expansion of PSG gene families appear to be a highly active process, with significant changes in gene numbers and protein domain structures in different mammalian lineages and reports of extensive copy number variation at the human locus. Against this apparent diversification, the available evidence indicates extensive conservation of PSG functions in multiple species. These observations are consistent with maternal–fetal conflict underpinning the evolution of PSGs.

Introduction

The placenta is predominantly a fetal structure with diverse functions in maternal–fetal interactions. Fetal trophoblasts secrete hormones that may act locally in the placental bed or enter the maternal circulation and underpin endocrine functions (Carter 2012, Costa 2016, Napso et al. 2018). Many placental hormones are encoded by multigene families, whereas most hormones expressed in adult tissues are encoded by single genes (Rawn & Cross 2008). This striking observation could suggest that paralogous genes encode placental hormones with diverse functions, presumably through binding different or polymorphic receptors. An alternative explanation is that placental hormone gene family expansions are driven by selection for increased dosage of the gene product (Haig 1993, 2008). Appreciating the selective forces that drive placental hormone gene family expansions is important for understanding their genomic organization, protein structures, expression patterns and functions.

The pregnancy-specific glycoprotein (PSG) gene families have been studied predominantly in the mouse and human but not in the same detail as other placental hormones (Moore & Dveksler 2014). Nevertheless, we can draw several conclusions. First, PSGs are undergoing active evolution, with recent gene family and protein domain expansions particularly evident in rodents, primates, equids and bats (McLellan et al. 2005, Zebhauser et al. 2005, Kammerer & Zimmermann 2010, Aleksic et al. 2016, Kammerer et al. 2017, Zimmermann & Kammerer 2021). Secondly, notwithstanding divergent protein domain structures between rodents, primates and equids, there appears to be considerable conservation of protein functions (Shanley et al. 2013, Warren et al. 2018, Kammerer et al. 2020). This suggests that PSGs have evolved to solve a significant challenge in the evolution of hemochorial placentation, which we have previously interpreted as a response to parent–offspring conflict (Moore 2012). However, the recent confirmation of PSG expression in the normal adult gastrointestinal (GI) tract complicates our understanding of PSG evolution because the selective forces underpinning adult gut expression are likely to be different to those acting on placental expression (Houston et al. 2016).

The nomenclature of PSGs was rationalized in 1999 (Beauchemin et al. 1999); therefore, earlier publications may have outdated gene name attributions. For example, PSG11 referred to in Arnold et al. (1999) has been reassigned as PSG9, whereas PSG11 in Zhao et al. (2012) is correctly named.

Historical work on PSGs has been summarized previously (Moore & Dveksler 2014). In the interim, the discovery of PSGs in equids, the identification of additional binding partners for human PSGs, the analysis of non-coding PSG transcripts and increasing evidence of PSG expression in non-placental sites, including tumors, suggest that an updated overview of PSG evolution and biology is warranted. Here, we outline and interpret recent findings, and we provide a critique of anti-PSG antibodies, which may become increasingly important tools in cancer studies.

PSGs are found predominantly in species with hemochorial placentation

Mammalian placentation is classified according to several criteria, including placental shape and the nature of the contact points between maternal and fetal tissues. Major placental types include diffuse epitheliochorial (e.g. horses, pigs), cotyledonary epitheliochorial (e.g. ruminants), zonary endotheliochorial (e.g. carnivores) and discoid hemochorial (e.g. primates, rodents). The defining feature of hemochorial placentation, which is found in the human and mouse, is the direct contact between maternal blood and fetal trophoblasts due to the invasion of trophoblasts through the maternal endothelium. This is the most invasive placental phenotype known, and in some species, the extravillous trophoblast (EVT) invades deeply into maternal tissues (Turco & Moffett 2019). For example, in the human, the EVT invades as far as the first third of the myometrium and there is extensive remodeling of the maternal spiral arteries and, to a lesser extent, veins and lymphatic vessels (Windsperger et al. 2017). PSGs appear to have evolved predominantly in species with hemochorial placentation (Fig. 1), and some of their functions may relate to challenges associated with the direct exposure of fetal trophoblast to maternal immune cells (Blois et al. 2014, Warren et al. 2018), to blood-borne pathogens (Zimmermann & Kammerer 2021) or to exposure of the mother to trophoblastic material which may be pro-inflammatory or pro-thrombotic (Burton & Jones 2009, Shanley et al. 2013).

Figure 1
Figure 1

Phylogenetic and taxonomic relationships of selected mammalian species (Murphy et al. 2001, Wildman et al. 2006). Type of placentation is indicated by the color of the branches of the phylogenetic tree. Total number of CEACAM/CEACAMpseudogenes and PSG gene family members identified is indicated. However, the varying qualities of genome sequences means that these numbers are provisional, and PSGs may ultimately be discovered in the species illustrated here with multiple CEACAM genes but no PSG data. PSG ancestors indicated by green dots.

Citation: Reproduction 163, 2; 10.1530/REP-21-0390

Equine PSGs – an exception that proves the rule?

The equine placenta is of the epitheliochorial type; however, an additional feature is the development of transitory trophoblastic structures, the endometrial cups, which develop around day 36 from the chorionic girdle and fully disappear by around day 130 (Antczak et al. 2013). Trophoblast cells invade through the basement membrane into the uterine stroma and secrete equine chorionic gonadotrophin, which is transferred to the maternal bloodstream via the lymphatic system. Intriguingly, the equine placenta is the only non-hemochorial placenta known to secrete PSG-like proteins (CEACAM44, 47, 48, 49, 55), many of which are expressed in the endometrial cups (Aleksic et al. 2016). Although there is no direct contact between the trophoblast and maternal blood, there is extensive invasion of the endometrial stroma and ensuing proximity to maternal immune cells. Functional convergence of the placenta-expressed equine proteins and human and mouse PSGs further strengthens the classification of the equine proteins as PSGs because the inhibition of platelet – fibrinogen interactions (Aleksic et al. 2016) – and activation of TGF-β (Kammerer et al. 2020), which are conserved functions of human and mouse PSGs, are not exhibited by non-placenta-expressed CEACAMs in any species.

PSGs are encoded by rapidly evolving multigene families

PSGs are encoded by multigene families in most species in which they occur (McLellan et al. 2005, Zebhauser et al. 2005, Kammerer & Zimmermann 2010, Aleksic et al. 2016, Kammerer et al. 2017, Zimmermann & Kammerer 2021; Fig. 1). There is extensive evidence of rapid evolution of PSG loci including differences in gene number, divergence of protein domain structures and content and non-conservative amino acid changes in open reading frames (McLellan et al. 2005, Zebhauser et al. 2005, Chuong et al. 2010, Kammerer & Zimmermann 2010, Aleksic et al. 2016, Kammerer et al. 2017, Zimmermann & Kammerer 2021). The human, mouse and horse PSG families have 11, 17 and 7 genes, respectively, and orthologous relationships are not evident between these species. However, some orthologous gene pairs can be identified between mouse and rat (Williams et al. 2015) and between human and apes (Zimmermann & Kammerer 2021). In addition to species-level divergence, the PSG locus may be the most prone to copy number variation in the human genome (Chang et al. 2013, Dumont & Eichler 2013).

Notwithstanding the rapid evolution of the PSG loci, the encoded proteins share many identical functions in all species examined, including in human, mouse and horse (Moore & Dveksler 2014, Aleksic et al. 2016, Kammerer et al. 2020). Therefore, the expansion and rapid evolution of PSG families are currently better explained by selection for increased gene product dosage than for diversification of functions. This selection pressure may be due to maternal–fetal conflict, in which placental hormones are secreted into the maternal circulation where they manipulate maternal physiology to the benefit of the fetus (Haig 1993, 2008, Moore 2012). An evolutionary arms race between fetal and maternal interests is predicted to drive high expression of fetal placenta-encoded hormones and a countervailing maternal strategy. Consistent with this, mouse Psg23 is undetectable in the maternal bloodstream of WT mice but reaches levels of up to 10 mg/mL in mutants with ablation of maternal liver asialoglycoprotein receptor (Mi et al. 2016).

Unlike in the mouse, human PSGs reach high steady-state levels in maternal blood (Towler et al. 1976, 1977, Rattila et al. 2019). It is unclear whether this represents the outcome of conflict or whether there has been selection for ancillary functions that may be beneficial to both the fetus and mother. For example, an anti-platelet action of PSGs may benefit both parties by counteracting platelet and endothelial activation and the propensity for thrombosis in the placental bed and maternal circulation (Shanley et al. 2013). More recently, a pathogen defense role for PSGs has been proposed (Zimmermann & Kammerer 2021), which would presumably benefit both mother and fetus. However, unlike the CEACAMs, some of which act as receptors and decoy receptors for pathogens (Zimmermann 2019), there is currently no evidence that PSGs bind to microorganisms.

PSGs are expressed in placental and non-placental tissues

The major site of PSG gene expression is the trophoblast of the fetal part of the placenta. Strong expression is seen in all examined trophoblastic lineages including rodent trophoblast giant cells and spongiotrophoblast, and human syncytiotrophoblast (Rebstock et al. 1993, Zhou et al. 1997a, Wynne et al. 2006, Blois et al. 2012, Williams et al. 2015). More recently, human PSGexpression has been reported in the human EVT, the trophoblast lineage that invades the endometrium (Rattila et al. 2019).

Presumably, due to the increasing bulk of trophoblast as pregnancy progresses, PSG levels in maternal plasma, which are undetectable by Western blot in the first trimester, reach levels greater than 100 μg/mL at term (Towler et al. 1976, 1977, Rattila et al. 2019). It is difficult to determine the relative amounts of different PSG proteins due to the lack of specific antibodies; however, the majority of transcripts in the first trimester are from PSG1 and PSG3, whereas at term PSG4, PSG5 and PSG6 are also strongly expressed (Shanley et al. 2013); others have reported broadly similar findings (Zimmermann & Kammerer 2021). Further complexity arises from the existence of multiple splice variants for each PSG gene. It is unclear what these differences mean, as most studies to date suggest conservation of functions of different PSGs; however, the deletion of PSG protein domains due to alternative splicing could have significant effects on protein function as there is some specialization across the various domains. For example, the human PSG B2 domain is largely responsible for TGF-β activation (Ballesteros et al. 2015).

In contrast to the high maternal blood levels of human PSGs, and notwithstanding high expression of the corresponding mRNAs, mouse Psg proteins were undetectable in maternal blood using an antibody raised against Psg23. That this is due to rapid turnover, rather than lack of mRNA translation or protein secretion, is suggested by the high levels of Psg proteins observed in the maternal blood of the asialoglycoprotein receptor 2 (ASGR)-deficient mice (Mi et al. 2016). However, it is possible that other mouse Psgs, not detected by the anti-Psg23 antibody used in this study, may be present at appreciable levels in maternal blood. In addition, it is unknown whether ASGR2 is responsible for the clearance of human PSGs.

Similar to gestational stage-specific expression of human PSGgenes, Psg gene expression in the first half of mouse pregnancy is almost exclusively Psg22 in trophoblast giant cells, with Psg16, Psg21 and Psg23 predominating in the spongiotrophoblast in the second half of pregnancy (Wynne et al. 2006). Mouse Psg protein functions appear to be conserved among different family members, although this has not been studied extensively. However, differences in CD9 binding have been described (Sulkowski et al. 2011), so further work may discover functional differences between different mouse Psgs.

Human PSG genes are expressed in non-placental tissues. Older work, using cDNA library screens, suggested that human PSG expression is widespread. However, those studies were not quantitative, and rare or aberrantly expressed transcripts may have been described. More recent analyses using array technologies and RNA-Seq provide more robust data. Scrutiny of the GTEx resource, which comprises data from multiple tissue samples from multiple adults, indicates very low expression of PSGs in various tissues as determined by RNA-Seq, including in the brain. Interestingly, PSG10, an expressed non-coding pseudogene which is closely linked to a brain-expressed lncRNA (PSG8-AS1), has minimal, but nevertheless more extensive, brain expression compared to other PSGs.

Mouse Psg16 (Phillips et al. 2012), but not its rat orthologues, PSG38 and PSG41, is widely expressed in the adult brain. Its function is unknown, and earlier reports that it is a receptor for coronavirus may be incorrect (Phillips et al. 2012). There is no evidence that other mouse or rat PSG family members are expressed in the brain.

GI tract expression of PSGs has been described in the human and mouse using RT-PCR, RNA-Seq and immunohistochemistry (Kawano et al. 2007, Houston et al. 2016). The strongest evidence of gut expression in the mouse is for Psg18, which is expressed in the follicle-associated epithelium overlaying Peyer’s patches, and which has been demonstrated using gene array analysis, qRT-PCR, in situ hybridization and immunohistochemistry. Psg18 protein is secreted and detectable in the extracellular matrix (Kawano et al. 2007).

Recently, PSG1 expression has been described in human skin, with increased expression in chronologically and photo-aged skin (Haydont et al. 2019). Interestingly, HeLa cells undergoing induced senescence, and human fetal lung fibroblasts undergoing replicative senescence, upregulate PSG mRNA expression, but this did not occur when the cells entered quiescence following serum withdrawal (Endoh et al. 2009). Transgenic over-expression of PSG4 and PSG6 in these cells appeared to confer partial resistance to various cellular stressors, suggesting a protective function, but their expression did not affect cell growth or morphology. We speculate that age-related expression may reflect either, or a combination of, chromatin deregulation at the PSG locus as previously suggested (Endoh et al. 2009) or recapitulation of features of the developmental program leading to PSG expression in vivo. Notably, fusion of placental cytotrophoblasts to form PSG expressing syncytiotrophoblast involves expression of senescence-related markers (Gal et al. 2019), and components of this pathway may be activated in aging or senescing somatic cells.

PSG activates TGF-β and binds multiple receptors – tetraspanins, integrins, syndecans and galectins

There has been recent progress in identifying binding partners of PSGs (Fig. 2). The tetraspanin CD9 binds to mouse PSG17 and PSG19 (Waterhouse et al. 2002, Ha et al. 2005, 2008, Sulkowski et al. 2011). Tetraspanins are implicated in multiple cellular processes including cell aggregation and motility, and signaling and fusion (Termini & Gillette 2017, Kummer et al. 2020). CD9 on the macrophage cell surface is required for PSG17-mediated induction of anti-inflammatory cytokine secretion (Ha et al. 2005). However, PSG17 binds to cell lines which lack CD9 expression, indicating more than one receptor for PSG17 as discussed below (Sulkowski et al. 2011). Interestingly, extensive CD9 expression in the pregnant uterus is found in maternal decidual and vascular tissues, suggesting that secreted mouse Psgs could bind to CD9 on maternal tissues (Wynne et al. 2006). Mouse PSG22 and PSG23, and human PSG1 and PSG11 do not bind to CD9; in the mouse, the CD9 binding site is in the region of highest divergence in the N1 domains of the PSGs (Ha et al. 2005, Wu et al. 2008, Lisboa et al. 2011, Sulkowski et al. 2011, Blois et al. 2012).

Figure 2
Figure 2

Structure and function of PSG1 domains. AlphaFold generated model of full-length PSG1 (P11464; https://www.nature.com/articles/s41586-021-03819-2), which is composed of four domains: N domain (blue) homologous to immunoglobulin variable domain, followed by three immunoglobulin C2-like domains (A1, green; A2, brown; B1, red). Seven potential N-glycosylation sites and three intra-domain disulfide bonds are indicated. Glycan profiles of N-glycosylation sites colored green (Asn61, 199, 268 and 303) have been characterized for maternal-serum-derived PSG1 (Mendoza et al. 2020). PSG1 binding partners and functions are shown in gray boxes; arrows indicate the specific PSG1 domains involved in each binding event.

Citation: Reproduction 163, 2; 10.1530/REP-21-0390

The first identified binding partners of human PSGs were glycosaminoglycans (GAGs), specifically heparin and heparan sulfate proteoglycans. PSG1 binding to cell surface syndecans 1–4 and glypican-1 was detected in solid phase assays and using fluorescence-activated cell sorting (FACS (Sulkowski et al. 2011, Blois et al. 2012). Binding of PSG1 to syndecans promotes proangiogenic endothelial tube formation (Lisboa et al. 2011, Rattila et al. 2020). In solid phase assays, the N1 domains of mouse PSG17, PSG22 and PSG23 also bind GAGs, which suggests conservation of a putative proangiogenic function between some human and mouse PSG family members (Sulkowski et al. 2011, Blois et al. 2012). In these experiments, the specific cell line used to produce recombinant mouse PSGs determined their ability to bind GAGs, suggesting that the type of N-linked glycans added to the proteins may affect their binding to charged GAGs (Sulkowski et al. 2011).

The presence of an Arg–Gly–Asp (RGD) tripeptide motif on a highly conserved and exposed loop in the N domain of the majority of human PSGs suggests that they bind integrins (Hammarström 1999). The RGD sequence is conserved in chimp and baboon PSG, but while mouse and rat PSG N1 domains do not have an RGD sequence, there are conserved RGD-like motifs (McLellan et al. 2005). PSG1 has a KGD motif (McLellan et al. 2005), which is also present in the southeastern pygmy rattlesnake venom disintegrin, barbourin (Scarborough et al. 1991). Human PSG1 and PSG9, mouse PSG23 and horse CEACAM49 (CC49) have been shown to bind the αIIbβ3 integrin on TRAP-activated human platelets in vitro, which suggests a conserved anti-thrombotic or anti-inflammatory function in vivo through inhibition of the platelet-fibrinogen interaction (Shanley et al. 2013, Aleksic et al. 2016). However, mutagenesis of the KGD motif and various protein domain deletions did not abolish the anti-platelet function of PSG1 indicating redundancy of integrin binding sites (Shanley et al. 2013).

Subsequently, it was shown that PSG1 binds integrin α5β1 and induces focal adhesion structures on trophoblast cells. PSG1 increases EVT migration and induces adhesion of primary EVT and two EVT‐like cell lines, HTR8/SVneo and Swan71 (Ratilla et al. 2019). It had previously been shown that PSG1 can bind to heparan sulfate proteoglycan in the ECM, and the finding that PSG1 can simultaneously bind α5β1 integrin and the highly sulfated heparin suggests that the adherence of EVT to the maternal decidua could involve PSGs as intermediaries (Ratilla et al. 2019).

PSGs are heavily glycosylated, and pooled native PSGs possess multi-antennary complex glycans which contain poly-N-acetyl-lactosamine (LacNAc) elongated moieties with mainly α2,3-linked sialic acid terminals and partial core-fucosylation (Mendoza et al. 2020). PSGs were hypothesized to bind galectins in a carbohydrate-dependent manner as both PSGs and galectin-1 (Gal-1) are secreted by the placenta and have immunomodulatory, angiogenic, and cell adhesion and motility functions (Mendoza et al. 2020). PSG1—Gal-1 interactions were confirmed using ELISA, mutagenesis and competition assays, and direct binding of human Gal-1 to native and recombinant PSG1 was confirmed using surface plasmon resonance (Mendoza et al. 2020). Use of recombinant single-domain PSG proteins, with and without treatment with PNGAse F, showed that the N and A2 domains are responsible for Gal-1 interactions. PSG1 protects Gal-1 activity from oxidation and may act as a competitive inhibitor of Gal-1 binding to fibronectin (Mendoza et al. 2020). Currently, it is unknown whether PSGs interact with other members of the galectin family.

There is an extensive literature showing PSG-mediated induction of cytokines, chemokines and angiogenic molecules in multiple cell types. Much of this work has been reviewed previously (Martinez et al. 2013, Moore & Dveksler 2014, Jones et al. 2019; Fig. 3). A key conserved function of PSGs is the upregulation of expression and functional activation of TGF-β. Human and mouse PSGs upregulate TGF-β1 expression in immune cells (Snyder et al. 2001, Motrán et al. 2002, 2003, Ha et al. 2005, 2008, 2010, Wu et al. 2008, Blois et al. 2012, Martínez et al. 2012, Martinez et al. 2013). In addition, PSG1 binds directly to the latency-associated peptide (LAP) of TGF-β1 and TGF-β2, mediated mainly through the PSG1 B2 domain (Ballesteros et al. 2015, Kammerer et al. 2020). ELISA and TGF-β reporter assays showed that all human PSGs and mouse PSG23 activate latent TGF-β1 (Warren et al. 2018). PSG1 and PSG4 and, potentially, other PSGs activate latent TGF-β1 bound to the extracellular matrix but not on membranes of the Jurkat T cell line, in which latent TGF-β1 is bound to GARP (Glycoprotein A repetitions predominant) (Warren et al. 2018). The horse PSG, CC49, also binds the LAP of both TGF-β1 and TGF-β2, and binding of CC49 leads to the activation of TGF-β1 as determined by ELISA and cell-based assays (Kammerer et al. 2020). The observation that PSGs increase the availability of active TGF-β1 and induce CD4+ Foxp3+ T regulatory cells in vivo and in vitro suggests a role in establishing maternal tolerance in pregnancy (Blois et al. 2014, Falcon et al. 2014, Jones et al. 2016, 2019).

Figure 3
Figure 3

Summary of immunomodulatory properties of PSG1.

Citation: Reproduction 163, 2; 10.1530/REP-21-0390

PSG10 and PSG7 non-coding transcripts: lncs and sinks?

An expectation from maternal–fetal conflict theory is that PSG genes are selected for high expression to maximize production of PSG proteins and their downstream phenotypic effects (Haig 1993, 2008, Moore 2012). The existence of non-coding PSG mRNA variants is therefore surprising. PSG10 has been characterized as an expressed pseudogene, PSG10P, because >99% of SNP rs1367178999 (T/A/C) alleles are the T variant which introduces a stop codon that severely truncates the open reading frame (Barnett et al. 1990, Wang et al. 2019). The retention of an expressed copy of the non-coding PSG10P might be explained by its transcript acting as a sink for microRNA miR‐19a‐3p (Wang et al. 2019), which regulates TGF-β1-mediated fibrosis, tumour metastasis and angiogenesis in various models (Zou et al. 2016, Jiang et al. 2018, Gollmann-Tepeköylü et al. 2020). Regulation of miR-19a-3p or other miRs by PSG10P may affect trophoblast differentiation or function, or the delivery of PSG10P to other cell types via trophoblast-derived exosomes might regulate non-trophoblastic tissues. Interestingly, human PSG10P orthologs in the chimpanzee and bonobo appear to have intact open reading frames (RK, unpublished observations).

PSG7 is annotated as a protein encoding gene but exon 2 contains SNP rs113247044 (G/A), with a major (A) allele frequency of 83%, which suggests that nearly 70% of individuals will have an AA genotype. The A allele results in a stop codon and, presumably, nonsense-mediated decay of the mRNA or termination of translation resulting in a severely truncated protein (Fig. 4). There are two possible modes of production of potentially viable shorter PSG7 proteins from the A allele: exclusion of exon 2 by alternative splicing or initiation of translation from a putative initiator AUG in exon 3. Alternatively, the non-coding PSG7 transcript may act as a lncRNA, similar to PSG10P; however, there are currently no data on these possibilities.

Figure 4
Figure 4

PSG7 SNP rs113247044 at the beginning of exon 2 creates a stop codon. The truncating allele is the most frequent in the population (81–86% according to 1000G, GnomAD, TOPMED, ExAC, GoESP, ALSPAC, TWINSUK, NorthernSweden databases). In a placenta gene expression data set (n = 39), genotypes were inferred from mRNA together with Hardy–Weinberg equilibrium estimates for genotype frequencies. Homozygotes for the A allele had considerably lower expression than heterozygotes.

Citation: Reproduction 163, 2; 10.1530/REP-21-0390

PSG expression in reproductive disorders

Early work on PSGs suggested that multiple pregnancy disorders (e.g. spontaneous abortion, ectopic pregnancy, intrauterine growth retardation, preeclampsia and fetal hypoxia) are associated with decreased PSG levels in maternal blood (Hertz & Schultz-Larsen 1983, MacDonald et al. 1983). However, other studies gave more ambiguous results, in which PSG levels were unchanged or were lower when associated with IUGR with or without preeclampsia (Chapman et al. 1981, Karg et al. 1981, Grudzinskas et al. 1983, Silver et al. 1993, Bersinger et al. 2003, Bersinger & Ødegård 2004, Pihl et al. 2009). Towler et al. (1977) estimated PSG levels in maternal blood at term at 200 μg/mL, with an increase noted in twin pregnancies. More recently, an increase in PSG9-derived peptides was noted in early-onset, but not in late-onset, preeclampsia (Blankley et al. 2013). However, lower levels of PSG1 were found in maternal serum of preeclamptic pregnancies compared to controls (Rattila et al. 2019, Temur et al. 2020). As discussed below, many of the earlier studies do not specify the origin of the anti-PSG antisera used, and claims regarding specificity must be treated with caution.

Other evidence associates PSG deregulation with preeclampsia. The mRNA levels of several PSGs were reduced in extravillous trophoblast, including invasive and endovascular subtypes dissected from severe PE cases (Gormley et al. 2017). More recently, PSG1 expression was reported in extravillous trophoblast (Rattila et al. 2019). Notably, lack of invasion of maternal endometrial arteries is a key observation in preeclampsia, and PSG1 co-localizes with integrin α5β1 (Rattila et al. 2019), which is thought to promote endometrial endovascular invasion by EVT (Zhou et al. 1997b).

Two studies implicate PSG9/PSG11 in reproductive disorders. PSG11 (now named PSG9) mRNA was low in the endometrium of patients with a history of recurrent abortion (Arnold et al. 1999). A genomic deletion of the maternal PSG11 locus was enriched in preeclampsia patients following a genome-wide scan of 169 cases and 114 controls (Zhao et al. 2012). However, it is unclear whether the association results from altered PSG11 expression in a maternal tissue such as endometrium or is secondary to the transmission of the deletion to the fetus with ensuing effects on trophoblastic PSG11 expression.

As noted earlier, non-coding PSG10P is upregulated in preeclampsia, where it may have a role in sequestering microRNA miR‐19a‐3p, leading to increased expression of IL1RAP, which could contribute to preeclampsia (Wang et al. 2019).

However, no clear conclusions can currently be drawn from the study of PSG genetics and expression in disorders of pregnancy due to a combination of underpowered studies, poorly characterized antibodies and the use of multiple different techniques, experimental designs and patient cohorts.

PSGs in cancer and gastrointestinal disease – emerging fields?

The involvement of the CEACAMs in cancer is well established and CEA/CEACAM5 is a widely used therapeutic biomarker (Li et al. 2010). The CEA-related PSGs are also expressed in cancers but the evidence that they contribute to tumorigenesis is limited. Older studies that relied exclusively on immunohistochemistry or ELISA assays with poorly characterized antibodies should be treated with caution (see below and Table 1). These studies suggested that PSG expression occurs in tumors of lung, GI tract, urinary tract, pancreas and breast tissue (Skinner & Whitehead 1981, Harach et al. 1983, Sorensen et al. 1984, Cohen et al. 1987, Campo et al. 1989, Boucher & Yoneda 1995).

Table 1

Specificity of selected anti-human PSG antibodies.

Antibody Vendor Protein domain recognized Reactivity Immunogen
Anti-PSG1 MAB6799 (M) R&D systems/Bio-Techne* Epitope present in both A1 and A2 All PSGs (W, E)

CEACAM5, 6, 7, 8 (E)
PSG1
Anti-PSG9 ab154733 (P) Abcam* Unknown PSG1, 4 ,6 ,7, 8 (W) Amino acids 74-293 of PSG9
Anti-PSG9 ab64425 (P) Abcam* N PSG6, 9 (W) Peptide spanning part of PSG9 N and A1 domains
Anti-PSG9 TA346332 (P) OriGene N PSG6, 9 (W) Peptide spanning part of PSG9 N and A1 domains
Anti-PSG9 NBP2-19980 (P) Novus Biologicals/Bio-Techne Unknown PSG1, 2, 3, 4, 6, 7, 8, 9 (W)

Does not detect PSG5 or 11 (W)

CEACAMs not tested
Peptide spanning part of N, all of A1 and part of A2 domains of PSG9
Anti-PSG6 AF8598 (P) R&D systems/Bio-Techne* Unknown All human PSGs (W)

CEACAMs not tested
PSG6
Anti-PSG9 NBP2-19979 (P) Novus Biologicals/Bio-Techne Unknown PSG1, 3, 4, 6, 7, 8, 9 (W)

Low reactivity with PSG5, 11, CEACAM5 and CEACAM6 (W)
Central region of PSG9
Anti-PSG1 NBP1-58028 (P) Novus Biologicals/Bio-Techne B2 B2 domain of PSG1 and PSG6 (W)

Other PSGs not tested
B2 domain peptide of PSG1
Anti-PSG9 NBP1-57676 (P) Novus Biologicals/Bio-Techne Unknown PSG9 and low reactivity with PSG6 (W)

Does not detect the other PSGs, CEACAM5 or CEACAM6 (W)
Peptide spanning part of PSG9 N and A1 domains
BAP-1 (M) Aldevron* A2 PSG1, 4, 8, 9

CEACAM1 (W, FC)

Other CEACAMS not tested
PSG1
BAP-3 (M)

GM-0507
Aldeveron*

OriGene
B2 PSG1 (W, FC), PSG3, 4, 6, 7, 8 (W) No reactivity to PSG2, 5 (W)

Can be used for IHC

Does not react to CEACAMs (FC, W)
PSG1
Ab #4 (M) n/a N (glycosylation required) PSG1, 2, 4, 6, 7, 8 (W)

Can be used for IHC

Does not bind CEACAM1 or CEACAM5
PSG1
Ab #5 (M) n/a N PSG1, 7, 8 (W)

Can be used for IHC
PSG1
Ab #11 (M) n/a A1 PSG1, 8

Can be used for IHC
PSG1

*indicates that the Ab is no longer sold by the indicated vendor; n/a indicates that the Ab is not commercially available.

E, ELISA; FC, flow cytometry; IHC, immunohistochemistry; M, monoclonal; P, polyclonal; W, Western blot.

More recently, using well-characterized monoclonal antibodies (mAbs), PSG expression in oesophageal and colonic adenocarcinomas was observed in histologically relatively normal tissue within the tissue section field, and PSG expression decreased as tumour grade increased (Houston et al. 2016). Nevertheless, PSG secretion could potentially promote tumourigenesis at earlier stages of the disease by acting on tumour cells, or on stromal or immune cells in the tumour microenvironment. The mAbs used in this study were raised against recombinant PSG1 and exhibited cross-reactivity to the closely related PSG7 and PSG8 proteins (Houston et al. 2016).

PSG9 deregulation has been reported in both sporadic colorectal cancer and in familial adenomatous polyposis (Salahshor et al. 2005, Yang et al. 2016). Yang et al. (2016) reported increased tissue expression and secretion into the bloodstream of PSG9 and described a mechanism comprising binding of PSG9 to SMAD4 and relocation to the cell nucleus, leading to activation of multiple angiogenesis genes. In this study, over-expression of PSG9 enhanced tumor growth in a mouse xenograft model. However, the source and specificity of the anti-PSG9 antibody was not stated. Also, the PSG9 protein used was made in bacterial BL21 cells, which may be problematic because PSG proteins are normally heavily glycosylated. A conceptually similar study in breast cancer also implicated the SMAD4/TGF-β1 pathway (Liu et al. 2020); again, however, the antibody used is not specific for PSG9 (GD & colleagues, unpublished observations; Table 1).

PSG deregulation was also observed in non-GI tract cancers in recent studies, supporting the earlier work mentioned above. The PSG locus harbors copy number variants in ~20% of cervical cancer samples, associated with increased expression of PSG2 and PSG5 (Marrero-Rodríguez et al. 2018). Increased expression of KLF10, which binds to PSG2 and PSG5 core promoters, also underpins PSG expression in the cervix, and mice homozygous null at the Klf10 locus have a deficit of Psg17, Psg21 and Psg23, indicating conservation of this regulatory mechanism (Marrero-Rodríguez et al. 2018).

PSG1 expression was found in the majority of pancreatic ductal adenocarcinoma samples examined using R&D Systems antibody MAB6799, and the staining pattern was correlated with patient survival (Shahinian et al. 2016). However, the specificity of this antibody is questionable (Table 1).

Anti-PSG antibody specificity

Confidence in the specificity of anti-PSG antibodies is important for interpreting published results and for future research. However, many of the antibodies used in earlier studies were poorly characterized and are no longer available for evaluation. Recently, individual recombinant PSG and CEACAM proteins have been generated for testing currently available antibodies (Houston et al. 2016, Warren et al. 2018). These studies indicate that the claims of specificity made by some commercial suppliers and in scientific publications are potentially invalid because the antibodies used were not tested against all PSG family members or against even a representative set of CEACAMs (Table 1). Moreover, the gold standard for specificity testing – the use of confirmed non-expressing cell lines or tissues generated, for example, using CRISPR mutagenesis – has not been reported for any anti-PSG antibody.

The extensively characterized BAP-3 mAb (Zhou et al. 1997a) recognizes the B2 domain of human PSG1, PSG3, PSG4, PSG6, PSG7 and PSG8 but not PSG2, PSG5, PSG9, PSG11, CEACAM1, CEACAM3, CEACAM5, CEACAM7 and CEACAM8 (GD & colleagues, unpublished observations; Table 1). The BAP-1 mAb recognizes the A2 domain of PSG1, PSG4, PSG8 and PSG9, and some CEACAMs (Zhou et al. 1997a).

Prof. Stipan Jonjic et al., University of Rijeka, Croatia, have produced a series of mAbs following immunization of mice with recombinant PSG1. Some have been characterized and appear to be PSG-specific, including mAb4, mAb5 and mAb11 (Houston et al. 2016, GD & colleagues, unpublished observations; Table 1). mAb4 binds an epitope of the N domain of PSG1 and detects, to varying degrees, recombinant PSG2, PSG4, PSG6, PSG7 and PSG8 but not other PSGs on Western blot. It was used to purify native PSG1 from the serum of pregnant women and to show equivalent functionality to stably transformed CHO cell-derived recombinant PSG1 produced in a bioreactor (Blois et al. 2014). mAb5 recognizes the N domain and detects recombinant PSG1, PSG7 and PSG8 on Western blot, whereas mAb11 recognizes an epitope in the A1 domain and detects PSG1 and PSG8 (Houston et al. 2016).

The availability of antibodies to non-human PSGs is limited. A polyclonal raised against recombinant mouse Psg23, which was made in insect Sf9 cells, stained trophoblast giant cells which express Psg22 mRNA almost exclusively, but not spongiotrophoblast, which expresses relatively high levels of Psg23 mRNA (Wynne et al. 2006). A polyclonal raised in rabbits against a 16-amino acid peptide of mouse Psg18 conjugated to BSA was used to demonstrate Psg18 expression in the follicle-associated epithelium overlaying Peyer’s patches (Kawano et al. 2007). Two anti-mouse Psg polyclonals were raised to recombinant Psg22, and Psg23 proteins composed of the N1 domain fused directly to the A domain in rabbits and rats, respectively. These have been used for immunohistochemistry and Western blotting but their specificity among the extensive mouse Psg and Ceacam families is uncertain (Blois et al. 2012, Mi et al. 2016).

In summary, due to the complexity of the PSG and CEACAM families and the sequence similarity between different human PSGs and regions of the CEACAM family proteins, extreme caution should be exercised when interpreting data generated using anti-PSG antibodies which have not been extensively characterized.

Conclusions

We derive several general conclusions from the recent work reviewed here. The rapid evolution of PSG gene copy number, their predominant placental expression in many species and the apparent conservation of function between human, mouse and horse PSGs remain consistent with PSGs evolving due to maternal–fetal conflict. However, the increasing number of identified interacting partners for human PSG proteins makes it more likely that species-specific or individual PSG protein functional differences will ultimately be discovered. The evidence that human PSG7 and PSG10 produce non-coding RNAs further broadens the functional repertoire of the gene family.

The evidence for non-placental expression of PSGs, particularly in the gut, is accumulating, and we speculate that a contribution to immunotolerance may provide a rationale for understanding this expression pattern. The evidence that PSG deregulation contributes to human diseases such as cancer or pregnancy disorders is weak but further work using well-validated reagents and more rigorous study designs may provide convincing data in future. However, perhaps because of their genomic and functional complexity, PSGs remain relatively neglected among reproductive and cancer biologists.

Declaration of interest

T M and G D are named on patents relevant to development of PSG proteins as therapeutics. T Moore is an Associate Editor of Reproduction and was not involved in the review or editorial process for this paper, on which he is listed as an author.

Funding

Original research on PSG7 reported here (Fig. 4) was conducted by M A B-R with the financial support of Science Foundation Ireland under Grant number 18/CRT/6214.

Author contribution statement

T M and G D conceived and wrote the paper. M A B-R analysed data on PSG7 (Fig. 4). M A B-R, J M W, M D and R K contributed to writing the paper and constructing figures. All authors read and approved the manuscript.

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  • Figure 1

    Phylogenetic and taxonomic relationships of selected mammalian species (Murphy et al. 2001, Wildman et al. 2006). Type of placentation is indicated by the color of the branches of the phylogenetic tree. Total number of CEACAM/CEACAMpseudogenes and PSG gene family members identified is indicated. However, the varying qualities of genome sequences means that these numbers are provisional, and PSGs may ultimately be discovered in the species illustrated here with multiple CEACAM genes but no PSG data. PSG ancestors indicated by green dots.

  • Figure 2

    Structure and function of PSG1 domains. AlphaFold generated model of full-length PSG1 (P11464; https://www.nature.com/articles/s41586-021-03819-2), which is composed of four domains: N domain (blue) homologous to immunoglobulin variable domain, followed by three immunoglobulin C2-like domains (A1, green; A2, brown; B1, red). Seven potential N-glycosylation sites and three intra-domain disulfide bonds are indicated. Glycan profiles of N-glycosylation sites colored green (Asn61, 199, 268 and 303) have been characterized for maternal-serum-derived PSG1 (Mendoza et al. 2020). PSG1 binding partners and functions are shown in gray boxes; arrows indicate the specific PSG1 domains involved in each binding event.

  • Figure 3

    Summary of immunomodulatory properties of PSG1.

  • Figure 4

    PSG7 SNP rs113247044 at the beginning of exon 2 creates a stop codon. The truncating allele is the most frequent in the population (81–86% according to 1000G, GnomAD, TOPMED, ExAC, GoESP, ALSPAC, TWINSUK, NorthernSweden databases). In a placenta gene expression data set (n = 39), genotypes were inferred from mRNA together with Hardy–Weinberg equilibrium estimates for genotype frequencies. Homozygotes for the A allele had considerably lower expression than heterozygotes.

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