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J. Biol. Chem., Vol. 280, Issue 21, 20752-20761, May 27, 2005

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A Novel Mechanism for Protein Delivery

GRANZYME B UNDERGOES ELECTROSTATIC EXCHANGE FROM SERGLYCIN TO TARGET CELLS^*

Srikumar M. Raja¶, Sunil S. Metkar, Stefan Höning||, Baikun Wang, William A. Russin**, Nina H. Pipalia, Cheikh Menaa, Mattias Belting, Xuefang Cao¶¶, Ralf Dressel||||, and Christopher J. Froelich¶

From the Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, the ^**Bio-imaging Facility, Department of Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois 60208, the Departments of ^||Biochemistry II and ^||||Immunogenetics, University of Göttingen, 37073 Göttingen, Germany, the ^¶¶Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri 63110, the Department of Biochemistry, Cornell University, New York, New York 10021, and the Department of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037

The molecular interaction of secreted granzyme B-serglycin complexes with target cells remains undefined. Targets exposed to double-labeled granzyme B-serglycin complexes show solely the uptake of granzyme B. An in vitro model demonstrates the exchange of the granzyme from serglycin to immobilized, sulfated glycosaminoglycans. Using a combination of cell binding and internalization assays, granzyme B was found to exchange to sulfated glycosaminoglycans and, depending on the cell type, to higher affinity sites. Apoptosis induced by purified granzyme B and cytotoxic T-cells was diminished in targets with reduced cell surface glycosaminoglycan content. A mechanism of delivery is proposed entailing electrostatic transfer of granzyme B from serglycin to cell surface proteins.

Received for publication, February 1, 2005 , and in revised form, March 14, 2005.

^* This work was supported in part by National Institutes of Health R01 Grant 5RO1AI04494-03 (to C. J. F.), Evanston Northwestern Healthcare Pilot Grant EH03-107 (to S. M. R.), and Deutsche Forschungsgemeinschaft Grant Gu 105/16-1 (to R. D.). 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.

These authors contributed equally to the experimental work.

^¶ To whom correspondence should be addressed: Evanston Northwestern Healthcare Research Inst., 2650 Ridge Ave., Evanston, IL 60201. Tel.: 224-364-7660; Fax: 847-570-8025; E-mail: c-froelich{at}northwestern.edu or s-raja{at}northwestern.edu.

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