The serpin proteinase inhibitor 8: an endogenous furin inhibitor released from human platelets.
The cornerstone of hemostasis is the ability of the organism to limit the enzymatic processes involved, thereby avoiding thrombosis. For this, anticoagulant systems in place involve serpins, such as PAI-1 and antithrombin III, which bind to their targeted serine proteases and limit their period of activity. We have previously identified the serine protease furin as a platelet-derived enzyme with an intrinsic role in platelet functions. We now report that furin enzymatic activity decreased rapidly following platelet activation, corresponding with the increase in formation of a high 180 M(r) SDS-stable complex composed of furin and the PI8 serpin. PI8 is shown to be a platelet-derived constituent, synthesized by megakaryocytes and stored in platelets prior to its release. Immunoprecipitation and purification of the PI8-furin complex confirmed their direct interaction and indicates that one of the roles of PI8 is to inhibit furin enzymatic activity. Furthermore, our findings demonstrate the inhibitory capacity of exogenous PI8 in platelet aggregation assays. The finding that PI8 is released by platelets and controls functional responses suggests a role for this serpin in platelet-regulated pathophysiological responses.
Immunology Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Julie
J
Leblond
Marie-Hélène
MH
Laprise
Simon
S
Gaudreau
Francine
F
Grondin
Walter
W
Kisiel
Claire M
CM
Dubois
D001792:Blood Platelets / Q000201:enzymology*; D002460:Cell Line; D045683:Furin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008533:Megakaryocytes / Q000201:enzymology; D015539:Platelet Activation; D010974:Platelet Aggregation; D011961:Receptors, Fc; D015843:Serpins / Q000378:metabolism*
C045281:IgA receptor; D011961:Receptors, Fc; C108403:SERPINB8 protein, human; D015843:Serpins; D045683:Furin