Protein C inhibitor may modulate human sperm-oocyte interactions

Protein C inhibitor (PCI) is a heparin-binding plasma serine protease inhibitor that was originally identified as an inhibitor of activated protein C. PCI has a broad protease specificity, inhibiting several proteases in hemostasis and fibrinolysis by acting as a suicide substrate. Recently it has been reported that proteases of the reproductive system, such as acrosin, prostate-specific antigen, and tissue kallikrein, can also be effectively inhibited by PCI. However, a direct relation between PCI and physiological events during fertilization has not yet been established. An attempt was made to monitor and localize the inhibition of the sperm protease acrosin by PCI. Localization experiments for PCI on epididymal spermatozoa showed that PCI is present on the acrosomal cap of human spermatozoa, which demonstrates the early presence of PCI in the male reproductive tract. Induction of the acrosome reaction in ejaculated human spermatozoa resulted in the disappearance of PCI from the plasma membrane overlying the acrosomal head and the appearance of a strict distribution at the equatorial segment of human spermatozoa. The activity of acrosin in sperm extracts could be effectively inhibited by PCI. Zona-binding assays showed that active PCI is able to block sperm-egg binding in a concentration-dependent manner. The combination of the potent inhibition of acrosin and sperm-egg binding by PCI and the localization studies suggested that PCI may protect spermatozoa against premature acrosome reaction and degradation, thereby modulating the acrosin activity so that it can coincide with binding to the oocyte.