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J. Biol. Chem., Vol. 279, Issue 14, 13402-13411, April 2, 2004

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Furin Is a Chemokine-modifying Enzyme

IN VITRO AND IN VIVO PROCESSING OF CXCL10 GENERATES A C-TERMINALLY TRUNCATED CHEMOKINE RETAINING FULL ACTIVITY^*

Paul J. Hensbergen, Dennis Verzijl, Crina I. A. Balog¶, Remco Dijkman, Roel C. van der Schors||, Elizabeth M. H. van der Raaij-Helmer, Mariena J. A. van der Plas**, Rob Leurs, André M. Deelder¶, Martine J. Smit, and Cornelis P. Tensen

From the Department of Dermatology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, the Division of Medicinal Chemistry, Free University, De Boelelaan 1083, 1081 HV, Amsterdam, the ^¶Department of Parasitology, Leiden University Medical Center, P. O. Box 9600, 2300 RC, Leiden, the ^||Department of Molecular Neurobiology, Free University, De Boelelaan 1087, 1081 HV, Amsterdam, and the ^**Department of Infectious Disease, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands

Chemokines comprise a class of structurally related proteins that are involved in many aspects of leukocyte migration under basal and inflammatory conditions. In addition to the large number of genes, limited processing of these proteins by a variety of enzymes enhances the complexity of the total spectrum of chemokine variants. We have recently shown that the native chemokine CXCL10 is processed at the C terminus, thereby shedding the last four amino acids. The present study was performed to elucidate the mechanism in vivo and in vitro and to study the biological activity of this novel isoform of CXCL10. Using a combination of protein purification and mass spectrometric techniques, we show that the production of C-terminally truncated CXCL10 by primary keratinocytes is inhibited in vivo by a specific inhibitor of pro-protein convertases (e.g. furin) but not by inhibition of matrix metalloproteinases. Moreover, CXCL10 is processed by furin in vitro, which is abrogated by a mutation in the furin recognition site. Using GTPS binding, Ca²⁺ mobilization, and chemotaxis assays, we demonstrate that the C-terminally truncated CXCL10 variant is a potent ligand for CXCR3. Moreover, the inverse agonist activity on the virally encoded receptor ORF74 and the direct antibacterial activity of CXCL10 are fully retained. Hence, we have identified furin as a novel chemokine-modifying enzyme in vitro and most probably also in vivo, generating a C-terminally truncated CXCL10, which fully retains its (inverse) agonistic properties.

Received for publication, November 24, 2003 , and in revised form, January 7, 2004.

^* This work was supported by Grants from the Dutch Cancer Society (RUL 2000-2168; to C. P. T.) and the Maurits and Anna de Kock Foundation. 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.

To whom correspondence should be addressed: Leiden University Medical Center, Sylvius Laboratory, Department of Dermatology, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. Tel.: 31-71-5271903; Fax: 31-71-5271910; E-mail: C.P.Tensen{at}lumc.nl.

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