Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin.
Human granzyme B (GrB) released from cytotoxic lymphocytes plays a key role in the induction of target cell apoptosis when internalized in the presence of perforin. Here we demonstrate that GrB also possesses a potent extracellular matrix remodeling activity. Both native and recombinant GrB caused detachment of immortalized and transformed cell lines, primary endothelial cells, and chondrocytes. Cell detachment by GrB induced endothelial cell death (anoikis). GrB also inhibited tumor cell spreading, migration, and invasion in vitro. Investigation into the underlying mechanism revealed that GrB efficiently cleaves three proteins involved in extracellular matrix structure and function: vitronectin, fibronectin, and laminin. In vitronectin, GrB cleaves after an Arg-Lys-Asp (RGD) motif, which is part of the integrin-binding site found in matrix proteins. We propose that targeting of the integrin-extracellular matrix interface by GrB may allow perforin-independent killing of target cells via anoikis, restrict motility of tumor cells, facilitate lymphocyte migration, or directly reduce virus infectivity. It may also contribute to tissue destruction in diseases in which extracellular GrB is evident, such as rheumatoid arthritis and atherosclerosis.
Buzza
Marguerite S
MS
Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Australia.
Zamurs
Laura
L
Sun
Jiuru
J
Bird
Catherina H
CH
Smith
A Ian
AI
Trapani
Joseph A
JA
Froelich
Christopher J
CJ
Nice
Edouard C
EC
Bird
Phillip I
PI
D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D053804:Granzymes; D006801:Humans; D006868:Hydrolysis; D007797:Laminin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism*
D005353:Fibronectins; D007797:Laminin; D011994:Recombinant Proteins; D019096:Vitronectin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases