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Journal of Virology, March 2003, p. 3131-3147, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3131-3147.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human Herpesvirus 8 Envelope Glycoprotein B Mediates Cell Adhesion via Its RGD Sequence

Fu-Zhang Wang, Shaw M. Akula, Neelam Sharma-Walia, Ling Zeng, and Bala Chandran*

Department of Microbiology, Molecular Genetics and Immunology, The University of Kansas Medical Center, Kansas City, Kansas 66160

Received 6 August 2002/ Accepted 4 December 2002

Human herpesvirus 8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus, implicated in the pathogenesis of Kaposi's sarcoma, utilizes heparan sulfate-like molecules to bind the target cells via its envelope-associated glycoproteins gB and gpK8.1A. HHV-8-gB possesses the Arg-Gly-Asp (RGD) motif, the minimal peptide region of many proteins known to interact with subsets of host cell surface integrins. HHV-8 utilizes {alpha}3ß1 integrin as one of the receptors for its entry into the target cells via its gB interaction and induces the activation of focal adhesion kinase (FAK) (S. M. Akula, N. P. Pramod, F.-Z. Wang, and B. Chandran, Cell 108:407-419, 2002). Since FAK activation is the first step in the outside-in signaling necessary for integrin-mediated cytoskeletal rearrangements, cell adhesions, motility, and proliferation, the ability of HHV-8-gB to mediate the target cell adhesion was examined. A truncated form of gB without the transmembrane and carboxyl domains (gB{Delta}TM) and a gB{Delta}TM mutant (gB{Delta}TM-RGA) with a single amino acid mutation (RGD to RGA) were expressed in a baculovirus system and purified. Radiolabeled HHV-8-gB{Delta}TM, gB{Delta}TM-RGA, and {Delta}TMgpK8.1A proteins bound to the human foreskin fibroblasts (HFFs), human dermal microvascular endothelial (HMVEC-d) cells, human B (BJAB) cells, and Chinese hamster ovary (CHO-K1) cells with equal efficiency, which was blocked by preincubation of proteins with soluble heparin. Maxisorp plate-bound gB{Delta}TM protein induced the adhesion of HFFs and HMVEC-d and monkey kidney epithelial (CV-1) cells in a dose-dependent manner. In contrast, the gB{Delta}TM-RGA and {Delta}TMgpK8.1A proteins did not mediate adhesion. Adhesion mediated by gB{Delta}TM was blocked by the preincubation of target cells with RGD-containing peptides or by the preincubation of plate-bound gB{Delta}TM protein with rabbit antibodies against gB peptide containing the RGD sequence. In contrast, adhesion was not blocked by the preincubation of plate-bound gB{Delta}TM protein with heparin, suggesting that the adhesion is mediated by the RGD amino acids of gB, which is independent of the heparin-binding domain of gB. Integrin-ligand interaction is dependent on divalent cations. Adhesion induced by the gB{Delta}TM was blocked by EDTA, thus suggesting the role of integrins in the observed adhesions. Focal adhesion components such as FAK and paxillin were activated by the binding of gB{Delta}TM protein to the target cells but not by gB{Delta}TM-RGA protein binding. Inhibition of FAK phosphorylation by genistein blocked gB{Delta}TM-induced FAK activation and cell adhesion. These findings suggest that HHV-8-gB could mediate cell adhesion via its RGD motif interaction with the cell surface integrin molecules and indicate the induction of cellular signaling pathways, which may play roles in the infection of target cells and in Kaposi's sarcoma pathogenesis.

* Corresponding author. Mailing address: Department of Microbiology, Molecular Genetics and Immunology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7420. Phone: (913) 588-7043. Fax: (913) 588-7295. E-mail: bchandra{at}kumc.edu.

Journal of Virology, March 2003, p. 3131-3147, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3131-3147.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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