A plasma proteolysis pathway comprising blood coagulation proteases

Abstract

Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid β1-42 (Aβ1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes. Therefore, FXII and FVIIa serve as the sensor/initiator and executioner, respectively, for the proteolysis pathway. Moreover, activation of this pathway by one probe leads to the degradation of all three probes. Significant activation of this pathway follows tissue injury and may also occur in other disorders, e.g., Alzheimer's disease, of which Aβ1-42 is a key driver. However, enoxaparin, a clinically used anticoagulant, inhibits the proteolysis pathway and elevates plasma levels of the probes. Enoxaparin may also mitigate potential impact of activators of the proteolysis pathway on coagulation. Our results suggest that the proteolysis pathway is important for maintaining low levels of various plasma proteins. Our finding that enoxaparin inhibits this pathway provides a means to control it. Inhibition of this pathway may facilitate the development of disease biomarkers and protein therapeutics, e.g., plasma Aβ1-42 as a biomarker of Alzheimer's disease or recombinant human prolidase as an antitumor agent.

PEPD is a pivotal regulator of p53 tumor suppressor

“…We recently found that PEPD is a ligand of ErbB1 and ErbB2 which are oncogenic receptor tyrosine kinases, that the enzymatic function of PEPD is not needed for this activity, and that intracellular PEPD has no effect on these receptors 8 – 10 . It remains unclear about the physiological importance of PEPD as a ligand of ErbB1 and ErbB2 or the involvement of these receptors in PD, as circulating PEPD level is kept low by a plasma proteolysis pathway 11 . However, recombinant human PEPD or an enzymatically inactive mutant, when added to cell culture or injected to tumor-bearing mice (with inhibition of the plasma proteolysis pathway), strongly inhibits the growth of cancer cells overexpressing ErbB1 and/or ErbB2 9 , 10 , 12 .…”

Factor VII Gene Defects: Review of Functional Studies and Their Clinical Implications

“…FVII is a serine protease produced in the liver and presents in plasma as a zymogen at a concentration of 10 nM (0.5 µg/ml) [10][11][12] . This vitamin K-dependent glycoprotein is circulating in plasma in two forms, mainly as inactive single-chain zymogen and partly as active form (FVIIa) consisted of heavy and light chains.…”

Interactions of β-amyloid peptide with fibrinogen and coagulation factor XII may contribute to Alzheimer's disease

“…Aβ also binds to and activates coagulation factor XII (FXII), which can then initiate the contact system [39–43], a proteolytic cascade that leads both to clot formation through the intrinsic coagulation pathway and also to inflammation via bradykinin release after high molecular weight kininogen (HK) cleavage. Aβ-mediated activation of FXII could be one mechanism behind the increased contact system activation observed in the plasma and CSF of AD patients and mouse models [39, 40]…”