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Originally published In Press as doi:10.1074/jbc.M211579200 on January 6, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9283-9289, March 14, 2003
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Functional Activity of the Complement Regulator Encoded by Kaposi's Sarcoma-associated Herpesvirus*

O. Brad SpillerDagger §, David J. Blackbourn, Linda Mark||, David G. ProctorDagger , and Anna M. Blom||**

From the Dagger  University of Wales College of Medicine, Virus Receptor and Immune Evasion Group, Department of Medical Biochemistry, Heath Park, Cardiff CF14 4XX, United Kingdom, the  Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Church Street, Glasgow G11 5JR, United Kingdom, and the || Department of Clinical Chemistry, Lund University, University Hospital Malmö, Malmö S-205 02 Sweden

Kaposi's sarcoma-associated herpesvirus (KSHV) is closely associated with Kaposi's sarcoma and certain B-cell lymphomas. The fourth open reading frame of the KSHV genome encodes a protein (KSHV complement control protein (KCP, previously termed ORF4)) predicted to have complement-regulating activity. Here, we show that soluble KCP strongly enhanced the decay of classical C3-convertase but not the alternative pathway C3-convertase, when compared with the host complement regulators: factor H, C4b-binding protein, and decay-accelerating factor. The equilibrium affinity constant (KD) of KCP for C3b and C4b was determined by surface plasmon resonance analysis to range between 0.47-10 µM and 0.025-6.1 µM, respectively, depending on NaCl concentration and cation presence. Soluble and cell-associated KCP acted as a cofactor for factor I (FI)-mediated cleavage of both C4b and C3b and induced the cleavage products C4d and iC3b, respectively. In the presence of KCP, FI further cleaved iC3b to C3d, which has never been described before as complement receptor 1 only mediates the production of C3dg by FI. KCP would enhance virus pathogenesis through evading complement attack, opsonization, and anaphylaxis but may also aid in targeting KSHV to one of its host reservoirs since C3d is a ligand for complement receptor 2 on B-cells.

* This study was supported by grants from the Swedish Research Council (to A. B.), Kock's Trust, Österlunds Trust, Crafoord Trust, Royal Physiographic Society in Lund, Groschinsky's Trust, King Gustav V's 80th Anniversary Foundation, Zoega's Trust, and University Hospital in Malmö. This study was also supported by the Wellcome Trust Foundation, Cancer Research UK (to O. B. S. and D. J. B.) Grant C7934 and the Association for International Cancer Research Grant 01-242 (to D. J. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Wellcome Trust Career Development Fellow.

** To whom correspondence should be addressed. Tel.: 46-40-33-82-33; Fax: 46-40-33-70-44; E-mail: Anna.Blom@klkemi.mas.lu.se.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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