The human serpin (serine protease inhibitor) protein C inhibitor (PCI) is a secreted glycoprotein with broad protease reactivity and wide tissue distribution. Target proteases of PCI include proteases of the blood coagulation and fibrinolytic systems (e.g. thrombin, activated protein C, factor Xa, urokinase), tissue kallikreins, and the sperm protease acrosin. PCI is present in blood, urine, and most other body fluids. The highest PCI concentrations are found in seminal plasma. These data together with our finding that male homozygous PCI-deficient (knockout) mice are infertile (Uhrin et al. 2000) due to abnormal spermatogenesis, suggest that PCI is important for the regulation of male reproduction. However, studies in mice are limited by the fact that in adult mice PCI is exclusively expressed in the reproductive tract. In the human system PCI may therefore have additional, different functions.

PCI is a heparin-binding serpin, and in vitro glycosaminoglycans modulate not only its activity but also its target enzyme specificity. We have recently shown that PCI also binds to negatively charged/oxidized phospholipids. Phospholipid binding involves the heparin-binding site (H-helix) of PCI, and PCI-binding phospholipids influence PCI activity in a way similar to heparin (Malleier et al. 2007). Furthermore, PCI can be internalized by cells via a non-conventional mechanism involving the phospholipid phosphatidylethanolamine (Baumgärtner et al. 2007). Internalized PCI can translocate to the nucleus, and this nuclear targeting requires basic amino acids of the H-helix. By using yeast-2-hybrid screening we have identified JFC-1 (synaptotagmin-like protein 1, Slp1) as an intracellular partner of PCI. JFC1 is a phospholipid-binding protein and an effector molecule of the small GTPase Rab27a, which is involved in vesicular transport processes in the cell. Additional intracellular interaction partners of PCI are CSN5 and CSN6, both components of the Cop9 signalosome, which colocalize with PCI in the nucleus of lymphocytes.

In order to determine the biological role of PCI we therefore have to consider its interaction not only with glycosaminoglycans, but also with phospholipids, which may act as locally inducible regulators of PCI activity and specificity e.g. at sites of inflammation and/or apoptosis. Additionally phospholipids may regulate the inhibition of transmembrane serine proteases by PCI, and may also present a link to so far unrecognized intracellular actions of PCI.