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J. Biol. Chem., Vol. 280, Issue 25, 23549-23558, June 24, 2005
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Extracellular Matrix Remodeling by Human Granzyme B via Cleavage of Vitronectin, Fibronectin, and Laminin*
From the
Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Australia, ¶The Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Parkville 3052, Victoria, Australia, the **Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne 8006, Australia, and the Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201
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.
Received for publication, October 22, 2004 , and in revised form, March 2, 2005.
* This work was supported in part by grants from the National Health and Medical Research Council (Australia). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
A recipient of the Australian Post-Graduate Award.
|| Supported in part, by a grant from the Anti-Cancer Council of Victoria (Australia).
To whom correspondence should be addressed. Tel.: 61-3-9905-3771; Fax: 61-3-9905-3726; E-mail: phil.bird{at}med.monash.edu.au
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