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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. v.34 n.3-4 Santiago  2001 

Human epididymal proteins and sperm function during
fertilization: un update


1 These authors have equally contributed to the work
2 Instituto de Biología y Medicina Experimental (IBYME)
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Vuelta de Obligado 2490 (1428) Capital Federal. Argentina.
* Departamento de Ciencias Biológicas. Facultad de Ciencias Exactas y Naturales.
(Biol Res 2001; 34 3-4: 165-178)

Correspondence to: Mónica H. Vazquez-Levin, Ph.D. Vuelta de Obligado 2490. 1428-BUENOS AIRES, ARGENTINA. Phone (54-11)47832869. Fax (54-11)47862564. Email:

Received : June 7, 2001. In Revised form : July 3, 2001. Accepted: July 9, 2001


In contrast to the majority of invertebrates as well as vertebrates with external fertilization, most mammalian spermatozoa that have completed their morphogenesis in the testis are immotile and unable to interact with the egg. The acquisition of sperm fertilizing ability has been associated to metabolic and structural changes in the male gamete, particularly those occurring at the plasma membrane. These modifications take place during sperm transit through the epididymis in a complex process called sperm maturation (for reviews: Cooper, 1986; Robaire and Hermo, 1988). The sperm maturation process is followed by further changes occurring during ejaculation and in the female tract. The latter has been collectively called sperm capacitation (Yanagimachi, 1994).

The epididymis, a single convoluted duct, has been grossly divided into three major regions: caput, corpus, and cauda: they have been primarily distinguished by their epithelial cell morphology, their sperm fertilizing ability, and more recently, by their specific pattern of gene expression. The epididymis provides a luminal microenvironment for sperm maturation and storage under androgen control (Robaire and Hermo, 1988; Robaire and Viger, 1995; Tezón and Blaquier, 1981; Vazquez et al, 1986a,b, 1989). Numerous studies done in animals have suggested that specific secretory proteins produced in the epididymis associate to spermatozoa during transit through the organ and play a key role in the mammalian sperm maturation process by conferring the male gamete the ability to recognize the oocyte (Orgebin Crist and Fournier Delpech, 1982; Cuasnicú et al, 1984a,b,c, 1990; Gonzalez Echeverria et al, 1984; Moore 1981; Moore and Hartmann, 1986; Rochwerger et al, 1990). In humans, the existence of a sperm maturation process has been reported (Hinrichsen and Blaquier, 1980; Moore et al, 1983), and the synthesis and secretion of glycoproteins has been documented (Tezón et al, 1985a,b, 1987; Allen-Hoffmann and Mosher, 1987; Cooper et al, 1988; Ross et al, 1990; Moore et al, 1992; Miranda and Tezón, 1992; Boué et al, 1995, 1996; Miranda et al, 1995). Epididymal sperm-coating proteins may exert their effects on the male gamete already in the epididymis or become functional in the female tract. Some of the proteins produced by the epididymis, called sperm decapacitating factors, may associate to the cell surface and prevent premature sperm activation. Other epididymal proteins may act directly in the process of gamete recognition and interaction, by remaining on spermatozoa to mediate sperm binding to the zona pellucida and oocyte plasma membrane. Additionally, there are evidences suggesting an indirect participation of epididymal proteins upon fertilization (e.g. the alteration of the sperm surface by glycosylation, hydrolysis, lipid removal etc., see below). In addition to this role of the epididymis on sperm maturation, a system of regulated storage of spermatozoa in the distal region of the organ has been developed in mammals, ensuring that the stored cells are quiescent and unreactive (Bedford and Yanagimachi, 1991).

In the last ten years, the field of research on epididymal proteins and their function has advanced to the molecular level. There have been several reports characterizing epididymal proteins in different species. For some of them, the apparent molecular weight and their isoelectric point have been determined. In addition, immunolocalization with specific antibodies and, more recently, cDNA cloning and in situ hybridization have been done to determine the nucleotide sequences of the encoding genes as well as the amino acid composition of proteins of interest and their pattern of expression. Finally, cross-specie homology analysis has suggested their conservation as well as possible functions of these proteins. Rodents have been primarily the animal models in many studies. However, identification of homologous gene products in other mammals, particularly humans, has been difficult, in part by poor evolutionary conservation. An important recent development has been the use of specific cDNA libraries to examine gene expression in the human epididymis (see Kirchhoff, 1999; Légaré et al, 1999). However, the identity and function of epididymal secretory proteins in sperm maturation and the mechanisms by which their genes are controlled have yet not been completely elucidated.

This review is aimed at summarizing some aspects of the biochemical, molecular, and functional characterization recently completed in a group of human epididymal proteins, in the light of their potential role in the sperm maturation process, with special interest in their participation in the interaction with the zona pellucida, and in the sperm-egg fusion process.



Interaction with the zona pellucida

Capacitated spermatozoa initially interact, in a specie-specific manner, with the zona pellucida (ZP), an extracellular coat that surrounds all mammalian eggs. This process, called primary binding, is mediated by ZP glycoconjugates that recognize sperm receptors located on the surface of the male gamete. Bound spermatozoa undergo the acrosome reaction, and initiate penetration of the ZP. Sperm penetration involves digestion of the ZP and vigorous sperm motion, while keeping the sperm associated to the matrix, via sperm receptors; this interaction has been named secondary binding (Yanagimachi, 1994; Wassarman, 1999; Brewis and Wong, 1999). Numerous candidates have been postulated as sperm receptors for primary and secondary binding. Several proteins of epididymal origin proposed for these roles are described in the following paragraphs, and summarized in Table 1.


P34H is a 34 KDa human epididymal sperm protein synthesized and secreted predominantly by the principal cells in the proximal and distal section of the corpus epididymis. The predicted amino acid sequence reveals a high similarity with members of the short chain dehydrogenase / reductase family proteins. Moreover, it shows 65% identity with P26h, the hamster counterpart (Légaré et al, 1999). P26h has been characterized at the molecular level (Gaudreault et al, 1999), and its participation in the sperm _ egg interaction process has been well studied (Bérubé and Sullivan, 1994; Bégin et al, 1995; Bérubé et al, 1996). Immunocytochemical analysis with a polyclonal anti-P26h antibody shows a faint staining in human spermatozoa from the caput, while the majority of the cells in the cauda epididymis are stained, with a signal restricted to the acrosomal cap. The staining remains in capacitated spermatozoa, but apparently is lost during the acrosome reaction (Boué et al, 1994,1996). The presence of anti-P26h significantly reduced the ability of human spermatozoa to bind to homologous ZP, without affecting sperm acrosome reaction and fusion to the oolema (Boué et al, 1994). Finally, staining with anti-P26h has allowed the identification of infertile patients showing reduced P34H levels (Boué and Sullivan, 1996). Altogether, these evidences would suggest that P34H is a human epididymal protein involved in sperm interaction with the ZP.


N-acetylglucosaminidase (NAG, E.C. its a glycosidase reponsible for the hydrolysis of non reducing terminal N-acetylglucosamine (GlcNAc) residues from ß-glycosidic boundaries in numerous glycoconjugates. In mammals, the enzyme NAG is named ß-hexosaminidase (Hex, E.C., since it also hydrolyses N-acetylgalactosamine. The significance of this enzyme upon normal epididymal function has been suggested by the severe anomalies observed in Hex-knock out mice (Trasler et al, 1998; Adamali et al, 1999a, 1999b). Moreover, several experimental evidences would support its involvement in the participation of GlcNAc residues on human sperm-ZP interaction (Miranda et al, 1995, 1997,2000). It was found that incubation of capacitated spermatozoa with bovine serum albumin (BSA)GlcNAc (Brandelli et al., 1994) triggers the acrosome reaction, following a mechanism that resembles induction by homologous ZP (Brandelli et al, 1994, 1996). Moreover, preincubation of capacitated spermatozoa with GlcNAc was found to inhibit their ability to interact with the ZP (Miranda et al, 1997). The human epidydimal enzyme has been characterized at a biochemical level (Miranda et al, 1995). Recently, participation of Hex in early events of sperm-oocyte interaction has been suggested by studies showing that gamete incubation in the presence of human recombinant Hex or its substrate precludes the interaction of human spermatozoa with homologous ZP (Miranda et al, 2000). However, whether the epididymal enzyme is responsible for such role on the sperm-ZP interaction process remains to be demonstrated.

Table 1
Human sperm proteins of epididymal origin proposed to interact with the ZP.




on spermatozoa
Identity Homology with
other species


and others
Acrosomal cap of
ejaculated spermatozoa.
Decrease along the
Absent in acrosome
reacted cells

short chain

hamster: 65% to
pig: 71% to
reductase of lung






110 E Entire head of
ejaculated cells.
Increased in
capacitated cells.
Unique No


15-25 E: CO.

Entire spermatozoa
without changes during
or after capacitation or
acrosome reaction


18-19 E: CU and
Ejaculated cells: neck
and tail.
Acrosome reacted cells:
neck, tail and acrosomal

*E: epididymis (CA: caput, CO: corpus; CU: cauda). T: testis


The monoclonal antibody (mAb) named mAb4A8 was selected for its ability to inhibit human sperm-egg binding and penetration in a dose-dependent manner. It recognizes an epitope in a human epididymal and sperm surface protein not fully characterized. The antibody was found to specifically stain epithelial cells of the human epididymis and the spermatozoa in the lumen. Non glycosylated seminal plasma showed a weak reactivity in a 110 KDa protein band, while antigenic polypeptides of 78, 56 and 44 KDa were identified in glycosylated seminal plasma proteins (Batova et al, 1998). No further studies have been reported upon its role in fertilization.


The mAbIG12 was selected for its ability to immobilize and agglutinate human spermatozoa. Independently of these effects, a blockage of in vitro fertilization was observed in the presence of the antibody. The inhibitory effect was evidenced in a diminished sperm binding and penetration into the ZP. Moreover, a decrease in the number of sperm penetrations in the ZP free-hamster egg sperm penetration assay was seen in the presence of mAb IG12. Immunostaining of ejaculated spermatozoa reveals a positive granular pattern over the entire surface of the cell. By immunohistochemistry, mAbIG12 strongly stained epithelial cells of the corpus epididymis. Moreover, mAbIG12 recognized a single band of under 15 KDa on deglycosylated sperm extracts (Komori et al, 1997). No other studies have been reported until the present time.


A sperm protein named SOB3 was identified using the mAbLB5 developed towards human sperm proteins. mAbLB5 stained the neck and flagellum of most spermatozoa and the acrosome of 10-20 % of the cells. In Western immunoblot analysis, it recognized two bands of 18 and 19 KDa in spermatozoa and cauda epididymis protein extracts. Presence of the antibody in an in vitro binding assay was associated with a decrease in the number of sperm bound to the ZP. Some of the studies would suggest that SOB3 may become accessible once spermatozoa have completed the acrosome reaction, and consequently, an involvement in secondary binding to the ZP has been postulated (Martin Ruiz et al, 1998). Recently, cloning and sequencing of SOB3 has been reported, revealing a single copy gene with 98% of homology with prepro-FALL39 and 100% homology of CAP18, two human genes which encode an antimicrobial protein (Hammami-Hamza, 2001). The authors suggest two roles for SOB3: sperm protection against bacterial injury and secondary binding to the zona pellucida.

Sperm-egg fusion proteins

Acrosome reacted spermatozoa that have completed zona pellucida penetration, reach the perivitelline space, bind and fuse to the egg plasma membrane, release the genetic material and initiate zygote development. Sperm fusion to the ooplasma has been associated to fusion events described in viral particles. Protein complexes with both functions, binding and fusion, would be present in both the egg and the spermatozoa and would interact with the counterpart on the surface of the other gamete (Snell and White, 1996; Töpfer-Petersen, 1999). Sperm binding to the oolema has been proposed to involve interaction of sperm receptors located in the equatorial segment and postacrosomal region with carbohydrates from oligosaccharides located on the egg plasma membrane (Gabriele et al, 1998; Fusi et al, 1996). Several sperm adhesion molecules have been described, being the protein named fertilin the one best studied (Myles et al, 1994). Regarding the sperm-egg fusion process itself, the actual mechanism is yet unknown. As seen in studies done with virus, fusion proteins may have sequences of hydrophobic residues and mostly of alpha-helical structure (fusion peptides); interaction of the sperm fusion peptide with the egg plasma membrane could destabilize the membrane, following a process that would end with the formation of the fusion pore (Pecheur et al, 1999).Several proteins of epididymal origin have been proposed to participate in the sperm _ egg fusion process. Some of them are described in the following paragraphs and listed in Table 2.


Two different research groups have cloned a human epididymal secretory protein named ARP (AEG Related Protein) (Hayashi et al, 1996, Kratzschmar et al, 1996). This protein is the human counterpart of the well studied rat and mouse epididymal protein DE (named by Cameo and Blaquier, 1976; AEG, Acidic Epididymal Glycoprotein; Lea et al, 1978). DE has been characterized as a putative sperm receptor in the egg fusion process (Cuasnicú et al, 1984a,b,c; Rochwerger and Cuasnicú, 1992; Rochwerger et al, 1992; Perez-Martínez et al, 1995; Ellerman et al, 1998). Among others, ARP and DE belong to the CRISP family members that share a highly conserved cluster of cysteines near the carboxy-terminus. The epididymal origin and secretory nature of ARP, and its localization on the sperm head has suggested a participation for this protein in the fusion process. ARP has been detected on the human sperm head after the acrosome reaction (Cohen et al, 2000). Moreover, in the zona-free hamster egg sperm penetration assay, an anti-ARP antibody had an inhibitory effect upon the number of penetrating human spermatozoa. Using the recombinant ARP expressed in bacteria, human oocytes revealed in their surface the presence of complementary sites to ARP (Cohen et al, 2000). All these evidences strongly support a role of ARP in human sperm-egg fusion process.


Human sperm proteins of epididymal origin proposed to participate in sperm fusion to the


on spermatozoa
Identity Homology with
other species


30 E: CA,CO,CU postacrosomal
region of ejaculated
and acros reacted
cystein rich
rat: 38% to DE/AEG
mouse: 40.6% to CRISP1;
41.2% to Tpx1; 38.8% to
CRISP3 macaque: 85%
to mAEG


and 19
E: CA, CO.
ovary, placenta
Ejaculated spermatozoa:
postacrosomal region
and neck

rat: protein of 26 KDa
hamster: protein of 28KDa
rabbit: protein of 50 KDa


94-100 E: CA, CO. epidermal

macaque, rat, mouse
and rabbit (100 KDa)




Ejaculated spermatozoa:
head and sperm tail
Capacitated spermatozoa:
equatorial region
unique protein not found on
spermatozoa or tissue of


120-130 E

sperm head of ejaculated,
capacitated and acrosome
reacted spermatozoa

CAM rat / mouse: 90%


30-35 E: CA   RGD (Arg-

*E: epididymis (CA: caput, CO: corpus; CU: cauda). T: testis


The Sperm Oocyte Binding 2 protein (SOB2) has been purified using preparative electrophoresis of detergent extracts from human spermatozoa, after protein identification in Western immunoblotting with the mAbG12. The antibody specifically stained the epithelium and spermatozoa of the caput and corpus epididymis, but did not show any signal in testis and efferent ducts. The antibody did not have any inhibitory effect upon sperm motility, interaction with the ZP or the acrosome reaction. On the other side, mAbG12 Fab fragments were found to strongly inhibit binding and penetration of human spermatozoa to zona free-hamster oocytes (Boué et al, 1992; Lefèvre et al, 1997), suggesting a role of SOB2 in sperm-oocyte fusion.


A protein referred as FLB1 has been identified using a mAbCA6 raised against human sperm proteins. The epididymal protein was reported to be composed of two chains of 47 KDa and similar pI (5.8, 5.9), and was found to be homologous to cytokeratins 1 and 10. It was localized on the equatorial region of mouse, rat and hamster cauda epididymal spermatozoa, and in human, macaque, and rabbit ejaculated spermatozoa. It would progressively coat spermatozoa during their transit through the epididymis (Boué et al, 1995). In the presence of the mAbCA6, binding of human spermatozoa to zona free

hamster and human eggs was inhibited, without having an effect upon sperm forward progressive motility or cell interaction with the ZP (Boué et al, 1995).


A sialylglycoprotein of ~20 KDa (gp20) was purified by preparative electrophoresis of detergent extracts from human spermatozoa, and utilized to develop a polyclonal antiserum. The anti-gp20 antiserum allowed localization of the protein in capacitated spermatozoa over the equatorial segment in 90% of the cells. In addition, the strong staining seen in principal cells of the epithelial epididymis, but not in testis sections suggested its epididymal origin. In the zona free hamster egg sperm penetration assay, presence of anti-gp20 antibodies precluded sperm binding and penetration to the oocyte, again suggesting a role for this protein in the sperm-egg fusion process (Focarelli et al, 1998). GP20 was found to have in the N-terminal sequence a 100% homology with that of the lymphocyte antigen CDw52 (Hale et al, 1990). An evaluation using two dimensional electrophoresis and MALDI revealed two components of the gp20 sperm antigen (Focarelli et al, 1999).


Cadherins are a family of Cell Adhesion Molecules (CAM) known to specifically bind to other cadherins located on adjacent cells (Edelman, 1988; Takeichi, 1990). They are calcium dependent surface glycoproteins protected from proteolysis through stabilization by this ion, without which the molecule may undergo conformational changes making it susceptible to digestion (Takeichi, 1995). Cadherins have been involved in several signal transduction pathways through tyrosine kinases associated with adhesion sites, affecting association with the cytoskeleton (Salomon et al, 1992). To the present time, more than 40 different cadherin types have been identified. Among them, one of the major families is the epithelial cadherins (E-cad). Presence of E-cad in the human epididymal epithelium was demonstrated by immunohistochemistry (Anderson et al, 1994). In the rat, the mRNA encoding E-cad was found to be present and translated in the epididymis, differentially distributed in the tissue, and regulated by circulating androgens (Cyr et al, 1992). Recently, E-cad were reported to be present on the surface of both human gametes (Rufas et al, 2000). Characterization of the expression of human E-cadherin in the human male tract, and their role in the process of sperm interaction with the egg is currently under investigation in our laboratory.


The involvement of integrins in the interaction of spermatozoa with the oocyte plasma membrane has been supported by several findings. In particular, Bronson and Fusi (1990) first demonstrated that a ligand recognition motif for integrins, RGD (Arg-Gly-Asp), would participate in binding and penetration of human spermatozoa to zona free hamster oocytes. Moreover, RGD binding receptors were identified on the human egg plasma membrane (Fusi et al, 1992). Regarding human spermatozoa, it is known that testicular cells express ß3, ß5 and ß6 chains of ß1 integrin, and fibronectin, which is known to contain an RGD sequence (Schaller et al, 1993). Fibronectin has been identified as a epidydimal secretory protein and proposed as a marker of human sperm maturation (Miranda and Tezón, 1992).

Recently, using the strategy of differential epididymal cDNA library screening, novel specific human epididymal proteins containing four fibronectin type II (Fn2) modules were identified (Saalmann et al, 2001). In the report, homologous mRNAs were also found in several animal species. Moreover, a specific antipeptide antiserum recognized 30-35 kDa protein bands in extracts from human epididymal tissue, in fluid from the cauda, and in detergent extracts of ejaculated spermatozoa. In canines, a specific signal was also found in spermatozoa from the cauda epididymis, although no proteins were detected in protein extracts from caput spermatozoa. The role of this protein in sperm function has yet to be determined, though in bovine, binding of major proteins of the seminal plasma (BSP), which are similar but not homologous to this novel protein, would help sperm capacitation (Miller et al, 1990).

Table 3
Other human epididymal gene products


Localization on
proposed function
Homology with
other species


25-27 E: CO, CU Weak binding
to reacted
decapacitating factor,
maintaining the
cholesterol content
of male gametes
chimpanzee: EPI-1
96% pig: EP4


10 E:CO Acrosomal region unique Absent in rat, mouse,
cat, pig and marmoset


E: CA Weak binding unique absent in rat, dog,
horse, mouse and ram
pig: mRNA of HE3


10 E: CO, CU Weak binding decapacitating factor
"four disulfide core"
bovine: HE4-like
absent in rat-mouse


18-25 E: CU Ejaculated
tail, postacrosomal
CD52 antigen (99%)
protection from
immune attack
rat: SMEmG
mouse: B7 dog: CE5
Callitrix: mRNA
(from epididymis)


110 E glycoprotein receptor
signal transduction

insect: DHR 29%
rat, mouse, dog,
cat, horse


70-73 E bovine: ß-chain of
clusterin 60%
rat, mouse and ram




71-76 E:CA,CO,CU Whole cell secretory protein
gel formation of
ejaculated semen
rodents: seminal
vesicle secretory
guinea pig: GPI


8.5 E and others Head and tail
of ejaculated
Marker of defective
Ungulates, rodents,

  *E: epididymis (CA: caput, CO: corpus; CU: cauda). T: testis

Other human epididymis _ specific gene products (Table 3)


Using a strategy of differential secreening of human epididymal cDNA libraries, a set of six major secretory proteins of human epididymal epithelial cells, named HE1-HE6, were identified (Kirchhoff et al, 1990). With the exception of HE5, the others are novel (human) gene products, not previously reported in animal studies. A brief description of HE1, HE2, HE3, HE4, HE5, and HE6 molecular characterization is presented in the following paragraphs.

HE1: HE1 is a major secretory glycoprotein detected as a ~ 20 KDa protein, present within the epithelium and lumen of the corpus epididymis, and accumulated in the lumen of cauda epididymis and vas deferens. The mRNA encoding HE1 was found to be the most abundant gene product obtained using the strategy of differential screening. HE1 is well conserved among mammals (in chimpanzee, named EPI-1 (Perry et al, 1995; Fröhlich and Young, 1996) and boar, named EP4 (Parry et al, 1992) suggesting a common functional role in the mammalian epididymis. Moreover, HE1 N-terminus is almost identical to the same amino acid sequence of ram lipid transfer proteins, suggesting for HE1 a role in maintaining the high cholesterol content of spermatozoa during epididymal transit and storage (Kirchhoff et al, 1996).

HE2: The cDNA clone encoding HE2 was identified and characterized to encode a small secretory protein, specifically produced by the caput epididymal epithelium. Antibodies raised towards a recombinant HE2 produced in bacteria showed specific staining over the equatorial region of human ejaculated spermatozoa, suggesting its putative participation in sperm-oocyte interaction (Osterhoff et al, 1994). However, is it still not clear whether HE2 has a role in the sperm-egg interaction process, considering the lack of a significant effect of the HE2 antisera tested in the outcome of ZP binding test and the hamster egg sperm penetration assay (Kirchhoff, 1999).

HE3: Similarly to HE2, a major epididymal mRNA named HE3 encodes a Human Epididymal Protein 3, and predicts a small secretory glycoprotein (Mr 14900). HE3 is expressed in a highly regionalized manner in the epididymis. The epididymal caput is the region where it is abundant. Analysis of human genomic DNA has shown that HE3 presents three independent related genes, a, ß, g. However only a, b seem to be expressed by the human epididymis, while HE3-g probably is a nonfunctional pseudogene (Kirchhoff et al, 1994). Like HE2, HE3 is poorly conserved among mammals. The lack of homology with other known protein sequences makes difficult any speculation on its potential role in sperm maturation.

HE4: the cDNA sequence of a major human epididymis gene product called HE4 was described to encode a small (approximately 10 KDa) acidic secretory protein. The position of the half-cysteins suggested HE4 to be a two-domain member of the "four-disulfide core" or Whey Acidic Protein (WAP)-domain proteins, examples of which are HUSI-I/SLPI and guinea pig caltrin seminal plasma proteinase inhibitors (Kirchhoff et al, 1991). Anti HE4 antibodies give an specific signal in epididymal epithelium and duct lumen, as well as in the surface of ejaculated human spermatozoa. Dissociation of HE4 from the spermatozoa during capacitation would suggest a role as a decapacitating factor (Kirchhoff, 1998). A high nucleotide homology (76.8%) to HE4 was found in the rabbit protein BE-20, which was structurally related to extracellular proteinase inhibitors and only found in the epididymis (Fan et al, 1999).

HE5: The gene product HE5 was found to be abundant in the epithelial cells of the distal epididymis and deferent duct, in spermatozoa of the tubule, and in blood lymphocytes (Pera et al, 1996; Kirchhoff and Hale, 1996; Yeung et al, 1997). It is identical (99 % sequence homology) to the CD52 antigen which is expressed on the cell surface of human lymphocytes (Kirchhoff et al, 1993). HE5/CD52 transcripts are abundant only in the epididymis and vas deferens epithelial cells and in blood lymphocytes. Kirchhoff and Hale (1996) have proposed for HE5 a role in protection of spermatozoa from immune attack during maturation, storage and fertilization. The epididymal protein identified as gp20 has been found to be a homologue of HE5 (see above).

HE6: A novel gene product called HE6 was found to be expressed within the epithelial cells lining the human epididymal duct, mainly in the caput region. HE6 was found to be highly conserved among mammals. It shows homology with the seven-transmembrane-domain (Tm7) receptor superfamily, typical of the majority of G-protein_coupled cell-surface hormone receptors. Within the Tm7 family, HE6 shows low but significant homology to the secretin/VIP family. The predicted N-terminal extension was found to be longer than that of this family, and was similar to the highly glycosylated mucin-like surface molecules (Osterhoff et al, 1997). However, its possible involvement in the signal transduction mechanism remains to be determined.


Clusterin or sulphated glycoprotein-2 (SGP-2) is an abundant glycoprotein apparently produced by the testis, epididiymis and seminal vesicles (O´Bryan et al, 1994a). In the rat, the androgen regulation of SGP-2 and its sperm association in the epididymis suggests the presence of specific protein functions in this tissue and others where it is also expressed (Sylvester et al, 1991). Hermo et al (1991) have proposed that the testicular SGP-2 is released from spermatozoa when it leaves the seminiferous tubule and is removed by the epithelium of the rete testis and efferent ducts. Subsequently, SGP-2 is replaced by the protein secreted by the caput epididymis, suggesting a role in sperm maturation. Immunocytochemical studies on human spermatozoa revealed surface coating with the 80KDa conventional heterodimeric clusterin, while normal cells showed over the acrosomal cap a different form of clusterin which is reactive to a anticlusterin a-chain antibody (O´Bryan et al, 1994b). Participation of clusterin in the sperm-egg interaction process has yet not been reported.

GP83 and GP39

Using Wheat Germ Agglutinin (WGA), Concanavalin-A (Con-A) and (PNA) lectins, human epididymal proteins GP83 and GP39, named after their Mr, were identified. In tissue homogenates and epididymal fluids, WGA and Con-A recognized GP83 and GP39 while only GP39 was detected when using PNA. Moreover, an specific signal for GP83 and GP39 was obtained in sperm membrane extracts recovered from the corpus and cauda regions when using WGA (Liu et al, 2000). In a subsequent study (Sun et al, 2000), GP83 was purified from human seminal fluid and partially characterized. An specific antibody localized the protein in the corpus and cauda epididymis, specifically in the supranuclear region and cell membrane of principal cells as well in the luminal content. Immunolocalization of GP83 in spermatozoa showed an specific staining over the acrosome of ejaculated and capacitated cells, and a signal over the equatorial region in acrosome reacted spermatozoa, suggesting redistribution of the antigen. Participation of GP83 in the sperm _ egg interaction process has yet not been reported.


The semenogelins are predominant secretory proteins from the human seminal vesicles responsible for the gel formation of freshly ejaculated semen (Lilja and Laurell, 1984; 1985). In addition, the mRNA encoding SgII was detected, although in lower levels, in the caudal epididymal epithelium (Lilja et al, 1992; Bjartell et al, 1996). Moreover, SgII was localized in the posterior part of the head, midpiece, and tail of ejaculated spermatozoa (Bjartell et al, 1996). The role of SgII in the cauda region of the epididymis and on the spermatozoa remains to be established.


Ubiquitin, a 8.5 KDa protein, is a universal marker of proteolysis (Ciechanover, 1994). Recently, Sutovsky et al (2000, 2001a) demonstrated that ubiquitin secreted by the epididymal epithelium binds to the surface of defective spermatozoa, followed by phagocytosis of most ubiquitinated spermatozoa by epididymal epithelial cells. These findings of cell-surface ubiquitination in defective spermatozoa provides a possible mechanism for sperm quality control in mammals. Moreover, ubiquitination can be utilized as a new marker for semen abnormalities. In a recent report (Sutovsky et al, 2001b), a "sperm-ubiquitin tag immunoassay (SUTI)" was described as a valuable new tool for infertility diagnosis and prediction of IVF success in subfertile men diagnosed with idiopathic infertility.


This review has briefly shown some findings reported by several investigators on a set of human epididymal proteins identified and partially characterized in the recent years. The results suggest that the epididymis produces and secretes numerous proteins that would associate to the spermatozoa while they are transiting through the organ. These components would dramatically affect sperm functionality, allowing the male gamete to recognize the oocyte. However, much still is waiting to be done to comprehend this phenomenon. Implementation of genomics and proteomics will help, in the near future, to further characterize some already identified proteins, as well as to describe novel epididymal components, anticipating great advances in the elucidation of the sperm maturation process in humans.


This work was supported by grants from the World Health Organization (grant # 97175), the Agencia Nacional de Promoción de Ciencia y Tecnología (PICT97 00207), and the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) of Argentina (PIP 4404).


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