TY - JOUR
T1 - Antihemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor
AU - Buzza, Marguerite Stella
AU - Dyson, Jennifer Maree
AU - Choi, Hiuwan
AU - Gardiner, Elizabeth Ellen
AU - Andrews, Robert Keith
AU - Kaiserman, Dion
AU - Mitchell, Christina Anne
AU - Berndt, Michael Claude
AU - Dong, Jing-Fei
AU - Bird, Phillip Ian
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18577516
M3 - Article
VL - 283
SP - 22498
EP - 22504
JO - The Journal of Biological Chemistry
JF - The Journal of Biological Chemistry
SN - 1083-351X
IS - 33
ER -