Table 1.
Physiological functions of proteins in male accessory gland secretions potentially involved in regulating fertility in humans and rodents.
| Protein | Gene (human) | Gene (mouse) | Function | Phenotypes when mutated, overexpressed, or genetically ablated |
|---|---|---|---|---|
| Seminal vesicles | ||||
| SEMG1 | SEMG1 | Svs2 | SEMG1 forms intermolecular disulfide bridges with SEMG2 resulting in high molecular weight coagulum upon ejaculation [7]. Inhibits sperm motility [10, 11]. SVS2 is a known decapacitation factor and maintains sperm motility and sperm cholesterol levels, prevents spontaneous sperm capacitation, and is essential for sperm survival in the mouse uterus [66, 68] | SEMG1 variants (rs147894843, rs2301366) associated with infertility [57, 63]. Elevated SEMG1 precursor reported in oligozoospermic men [64]. Svs2−/− mice are subfertile with defects in copulatory plug formation [68] |
| SVS7 | SVS7 | Pate4 | SVS7 in mouse is essential for copulatory plug formation in vivo [69]. SVS7 enhances mouse sperm motility in vitro [70] | No known mutation/phenotype reported in humans. Pate4−/− mice are subfertile with defects in copulatory plug formation [69] |
| SERPINE2/PN1 | SERPINE2/PN1 | Serpine2/Pn1 | Serine protease inhibitor acts as a decapacitation factor [82]. Inhibits protein tyrosine phosphorylation and sperm capacitation [82] | Elevated PN1 levels in semen of men displaying seminal dysfunction [85]. Pn1−/− mice are infertile due to altered seminal protein composition and defects in copulatory plug formation [85] |
| SPINK3/SPINK1 | SPINK3/SPINK1 | Spink3/Spink1 | Serine protease inhibitor prevents premature acrosomal reaction and protects sperm in the uterine environment in mice [89, 90] | No known mutation/phenotype involving fertility reported in humans or mice |
| SPINKL | No known ortholog | Spinkl | Serine protease inhibitor acts as decapacitation factor and enhances sperm motility in mice [97] | No known mutation/phenotype involving fertility reported in humans or mice |
| Testis and epididymis | ||||
| EPPIN | SPINLW1 | No known ortholog | Localized on the sperm surface. Modulates KLK3 activity and acts as decapacitating factor [10, 78, 79]. EPPIN-bound SEMG1 crucial for SEMGs degradation and initiation of progressive sperm motility [11] | SPINLW1 upregulated in caput epididymis of non-obstructive azoospermic patients [80]. rs11594 variant associated with increased risk of idiopathic male infertility in Chinese–Han population [81]. |
| Epididymis | ||||
| SPINK2 | SPINK2 | Spink2 | Serine protease inhibitor protects sperm against protease activity during spermatogenesis | Homozygous SPINK2 mutation leads to azoospermia in men [86]. Decreased SPINK2 expression in azoospermic infertile men [87]. Spink2 mutant mice have elevated serine protease activity and exhibit impaired fertility [88]. Spink2−/− mice are azoospermic and infertile [86] |
| SPINK5 | SPINK5 | Spink5 | Serine protease inhibitor inhibits KLK5, 7, and 14 activities in corneocytes and regulates desquamation process [91, 92] | No known mutation/phenotype reported involving fertility in humans or mice |
| SPINK13 | SPINK13 | Spink13 | Serine protease inhibitor. Essential for acrosomal integrity, sperm maturation, and fertility in rats [96] | No known mutation/phenotype reported in humans. Spink13 knockdown rats demonstrate premature acrosomal reaction and reduced fertility [96] |
| Prostate gland | ||||
| KLK1 | KLK1 | Klk1/mGK6 | Serine protease | Low level observed in SHV samples [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK2/hK2 | KLK2 | No known ortholog | Serine protease cleaves fibronectin and SEMGs [42, 43]. Activator of pro-KLK3 [22–25]. Inhibited by Zn2+ [43] | Low KLK2 seminal levels observed in men with abnormal liquefaction and SHV [58]. SNP (rs2664155) associated with male infertility [61] |
| KLK3/PSA | KLK3 | No known ortholog | Serine protease. Major enzyme hydrolyzes SEMGs and fibronectin and liquefies semen coagulum facilitating sperm motility [8, 10, 36, 39–41]. Inhibited by Zn2+ [8, 41, 48] | Low KLK3 level observed in men with SHV [55, 57] and abnormal liquefaction [58]. Reduced sperm motility observed in men with low seminal KLK3 levels [59]. SNPs (rs266881, rs174776, rs1810020, rs266875, rs35192866) associated with male infertility [60] |
| KLK4 | KLK4 | Klk4 | Serine protease activates pro-KLK3 [26] | No known mutation/phenotype reported involving fertility in humans or mice |
| KLK5 | KLK5 | Klk5 | Serine protease. Initiates liquefaction cascade by activating downstream pro-KLK2, 3, 7, 8 and 14 [17, 21]. Cleaves fibronectin and SEMGs [21, 44]. Inhibited by Zn2+ [21] | Low level observed in SHV samples [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK6 | KLK6 | Klk6 | Serine protease exhibits catalytic activity towards fibronectin [46] | Low level observed in SHV samples in humans [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK7 | KLK7 | Klk7 | Serine protease exhibits catalytic activity towards fibronectin [47] | KLK7 (rs1654526) SNP associated with SHV in humans [57]. Low level observed in SHV samples in humans [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK8 | KLK8 | Klk8 | Serine protease | Low level observed in SHV samples [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK10 | KLK10 | Klk10 | Serine protease | Low level observed in SHV samples [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK12 | KLK12 | Klk12 | Serine protease | KLK12 (rs61742847) SNP associated with SHV [57]. No known mutation/phenotype reported involving fertility in mice |
| KLK13 | KLK13 | Klk13 | Serine protease exhibits catalytic activity towards fibronectin [44] | Low seminal levels observed in men with abnormal liquefaction and SHV [58]. No known mutation/phenotype reported involving fertility in mice |
| KLK14 | KLK14 | Klk14 | Serine protease. Activates pro-KLK1, 3, 5 and 11 [20, 27, 28]. Cleaves fibronectin and SEMGs [27, 28]. Inhibited by Zn2+ [28] | Low seminal levels observed in men with clinically delayed liquefaction, SHV, and asthenospermia [28, 58]. KLK14 inhibition by ACTG9 delays semen liquefaction [27]. No known mutation/phenotype reported in mice involving fertility |
| TGM4 | TGM4 | Tgm4 | A prostate-specific autoantigen plays a critical role in male reproduction and catalyzes the formation of N-ε-(γ-glutamyl)lysine cross-bridges between SEMGs in humans [72] and SVS proteins in mice [75], respectively | TGM4 autoantibodies are detected in subfertile adult male patients with autoimmune polyendocrine syndrome type 1, caused by mutations in autoimmune regulator (AIRE) gene [74]. Tgm4−/− mice are subfertile with defects in copulatory plug formation and seminal fluid viscosity [75]. Aire−/− mice develop TGM4 autoantibodies, compromised TGM4 secretion, prostatitis, and exhibit subfertility [74]. |