Novel Antimicrobial Peptide of Human Epididymal Duct Origin1

Horsten, Hans Henning von; Derr, Petra; Kirchhoff, Christiane

doi:10.1095/biolreprod.102.004564

Cited by 61 publications

(45 citation statements)

References 31 publications

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“…MUC15 overexpression in colorectal carcinoma cells enhances cell proliferation, cell extracellular matrix adhesion, colony-forming ability, and invasion (37). SPAG11B is a cationic secretory anti-microbial peptide expressed in human epididymis (38,39). FAM12B is an epididymal secretory protein (40,41) that has been found up-regulated in epididymides of nonobstructive azoospermic men (42).…”

Section: Discussionmentioning

confidence: 99%

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Drabovich

Jarvi

Diamandis

2011

Molecular & Cellular Proteomics

103

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Seminal plasma is a promising biological fluid to use for noninvasive clinical diagnostics of male reproductive system disorders. To verify a list of prospective male infertility biomarkers, we developed a multiplex selected reaction monitoring assay and measured the relative abundance of 31 proteins in 30 seminal plasma samples from normal, nonobstructive azoospermia and post-vasectomy individuals. Median levels of some proteins were decreased by more than 100-fold in nonobstructive azoospermia or post-vasectomy samples, in comparison with normal samples. To follow up the most promising candidates and measure their concentrations in seminal plasma, heavy isotope-labeled internal standards were synthesized and used to reanalyze 20 proteins in the same set of samples. Concentrations of candidate proteins in normal seminal plasma were found in the range 0.1-1000 g/ml but were significantly decreased in nonobstructive azoospermia and post-vasectomy. These data allowed us to select, for the first time, biomarkers to discriminate between normal, nonobstructive azoospermia, and post-vasectomy (simulated obstructive azoospermia) seminal plasma samples. Some testis-specific proteins (LDHC, TEX101, and SPAG11B) performed with absolute or nearly absolute specificities and sensitivities. Cell-specific classification of protein expression indicated that Sertoli or germ cell dysfunction, but not Leydig cell dysfunction, was observed in nonobstructive azoospermia seminal plasma. The proposed panel of biomarkers, pending further validation, could lead to a clinical assay that can eliminate the need for testicular biopsy to diagnose the category of male infertility, thus providing significant benefits to patients as well as decreased costs associated with the differential diagnosis of azoospermia. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.004127, 1-13, 2011.Human infertility affects ϳ15% of couples, with the male contributing to the infertility in 50% of all cases (1, 2). One of the most severe forms of male infertility is azoospermia, which is characterized by an absence of sperm in the semen (3). Azoospermia is diagnosed in 20% of subfertile men and has two forms: obstructive azoospermia (OA) 1 and nonobstructive azoospermia (NOA). OA is caused by a physical obstruction in the male reproductive tract. The biological outcome of OA is thus identical to that of vasectomy, which is a surgical severance of the vas deferens. NOA is a more complicated infertility syndrome with the azoospermia being secondary to a failure to produce sperm; NOA may be further subclassified as maturation arrest, Sertoli cell-only syndrome, and hypospermatogenesis (4).For most men with azoospermia, testicular biopsy is the only currently used method to definitively distinguish between OA and NOA (5, 6). Thus, there is an urgent need for an alternative noninvasive approach with better diagnostic potential. The differential diagnosis of normal, NOA, and OA (or post-vasectomy (PV)) men is required for the following reasons: (i) in infertile pati...

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Section: Discussionmentioning

confidence: 99%

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Drabovich

Jarvi

Diamandis

2011

Molecular & Cellular Proteomics

103

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“…hBD3 was isolated originally from inflamed human skin, is inducibly expressed in various epithelia (18,22,25,47), and possesses a broad spectrum of potent bactericidal activities in a salt-insensitive manner against both gram-positive and gramnegative bacteria (18,22,25,46). Genomics studies have identified several new members of the ␤-defensin family (28,40,53). Recently, a circular form of antimicrobial peptides, called -defensins, has been characterized in macaques, while in humans all the genes encoding these peptides contain stop codons and are therefore likely to constitute expressed pseudogenes (12).…”

mentioning

confidence: 99%

Human β-Defensins Suppress Human Immunodeficiency Virus Infection: Potential Role in Mucosal Protection

Sun

Finnegan

Kish-Catalone

et al. 2005

J Virol

224

228

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␤-Defensins are small (3 to 5 kDa in size) secreted antimicrobial and antiviral proteins that are components of innate immunity. ␤-Defensins are secreted by epithelial cells, and they are expressed at high levels in several mucosae, including the mouth, where the concentration of these proteins can reach 100 g/ml. Because of these properties, we wondered whether they could be part of the defenses that lower oral transmission of human immunodeficiency virus (HIV) compared to other mucosal sites. Our data show that select ␤-defensins, especially human ␤-defensin 2 (hBD2) and hBD3, inhibit R5 and X4 HIV infection in a dose-dependent manner at doses that are compatible with or below those measured in the oral cavity. We observed that ␤-defensin treatment inhibited accumulation of early products of reverse transcription, as detected by PCR. We could not, however, detect any reproducible inhibition of env-mediated fusion, and we did not observe any modulation of HIV coreceptors following treatment with hBD1 and hBD2, in both resting and phytohemagglutinin-activated cells. Our data instead suggest that, besides a direct inactivation of HIV virions, hBD2 inhibits HIV replication in the intracellular environment. Therefore, we speculate that ␤-defensins mediate a novel antiretroviral mechanism that contributes to prevention of oral HIV transmission in the oral cavity. Immunohistochemical data on hBD2 expression in oral mucosal tissue shows that hBD2 is constitutively expressed, forming a barrier layer across the epithelium in healthy subjects, while in HIV-positive subjects levels of hBD2 expression are dramatically diminished. This may predispose HIV-positive subjects to increased incidence of oral complications associated with HIV infection.

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“…These proteins have been shown to be processed when sperm cross the caput or corpus epididymis and to be involved in sperm fertility. We have also reported that several members of the matrix metalloproteases present in the epididymal fluid were activated from pro-to active forms after their transformation within the fluid (Metayer et al 2002a), and it has recently been demonstrated that an anti-microbial protein in human epididymal fluid and seminal plasma is processed in vivo and in vitro by furin (von Horsten et al 2002).…”

Section: Discussionmentioning

confidence: 93%

Analysis of furin ectodomain shedding in epididymal fluid of mammals: demonstration that shedding of furin occurs in vivo

Thimon¹,

Belghazi²,

Dacheux³

et al. 2006

Reproduction

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Sperm cell surface proteins and proteins of their surrounding fluids are reported to be proteolytically processed in relation to acquisition of sperm fertility during epididymal transit. Several of these proteins might be potential targets for subtilisin-like proprotein convertase. Using immunochemistry and mass spectrometry analysis, we found that an 80 kDa form of furin (EC 3.4.21.75) is present in the fluid from the mid-caput to the distal corpus regions of the epididymis of various domestic mammals. This protein is absent from the fluid of the caudal region, suggesting that it is reabsorbed or degraded. The cDNA sequence of ovine furin was obtained and the mRNA was found throughout this organ, although in greater amounts in the mid and distal caput regions. Metabolic labeling with 35 S-amino acids indicated that the protein was synthesized and released from the epithelium only in a restricted area of the mid-caput, suggesting a specific regionalized mechanism of secretion. The fluid protein is not pelleted at 100 000 g and did not react with a C-terminal antibody indicating that it is not bound to membranous materials. These findings demonstrate that a furin ectodomain shedding occurs naturally in vivo in the epididymis where this enzyme could be involved in fluid and/or sperm membrane protein processing.Reproduction (2006) 132 899-908

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Novel Antimicrobial Peptide of Human Epididymal Duct Origin1

Cited by 61 publications

References 31 publications

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Human β-Defensins Suppress Human Immunodeficiency Virus Infection: Potential Role in Mucosal Protection

Analysis of furin ectodomain shedding in epididymal fluid of mammals: demonstration that shedding of furin occurs in vivo

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