Antihemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor

Marguerite Stella Buzza, Jennifer Maree Dyson, Hiuwan Choi, Elizabeth Ellen Gardiner, Robert Keith Andrews, Dion Kaiserman, Christina Anne Mitchell, Michael Claude Berndt, Jing-Fei Dong, Phillip Ian Bird

Research output: Contribution to journalArticleResearchpeer-review

37 Citations (Scopus)

Abstract

The cytotoxic lymphocyte (CL) protease GrB (GrB) is elevated in the plasma of individuals with diseases that elicit a CL-mediated immune response. Given the recently-recognized ability of GrB to cleave extracellular matrix proteins, we examined the effect of GrB on the pro-hemostatic molecule von Willebrand factor (VWF). GrB delays ristocetin-induced platelet aggregation, and inhibits platelet adhesion and spreading on immobilised VWF under static conditions. It efficiently cleaves VWF at two sites within the A1-3 domains which are essential for the VWF-platelet interaction. Like the VWF regulatory proteinase ADAMTS-13, GrB-mediated cleavage is dependent upon VWF conformation. In vitro, GrB cannot cleave the VWF conformer found in solution but cleavage is induced when VWF is artificially unfolded or presented as a matrix. GrB cleaves VWF with comparable efficiency to ADAMTS-13 and rapidly processes ultra-large VWF multimers released from activated endothelial cells under physiological shear. GrB also cleaves the matrix form of fibrinogen at several sites. These studies suggest extracellular GrB may help control localized coagulation during inflammation.
Original languageEnglish
Pages (from-to)22498 - 22504
Number of pages7
JournalThe Journal of Biological Chemistry
Volume283
Issue number33
Publication statusPublished - 2008

Cite this