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Journal of Virology, November 2005, p. 13326-13337, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13326-13337.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Nasopharyngeal Carcinoma Cells, Epstein-Barr Virus LMP1 Interacts with Galectin 9 in Membrane Raft Elements Resistant to Simvastatin

Catherine Pioche-Durieu,1,{dagger} Cécile Keryer,1,{dagger} Sylvie Souquère,2 Jacques Bosq,3 Wolfgang Faigle,4 Damarys Loew,4 Mitsuomi Hirashima,5 Nozomu Nishi,6 Jaap Middeldorp,7 and Pierre Busson1*

UMR 8126 CNRS, Institut Gustave Roussy, Villejuif, France,1 CNRS UPR 1983, Institut André Lwoff, Villejuif, France,2 Département d'Anatomie Pathologique, Institut Gustave Roussy, Villejuif, France,3 Laboratoire de Spectrométrie de Masse, Institut Curie, 75005 Paris, France,4 Department of Immunopathology, Faculty of Medicine, Kagawa University, Japan,5 Department of Endocrinology, Faculty of Medicine, Kagawa University, Japan,6 Department of Pathology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands7

Received 1 May 2005/ Accepted 22 July 2005

Nasopharyngeal carcinomas (NPC) are etiologically related to the Epstein-Barr virus (EBV), and malignant NPC cells have consistent although heterogeneous expression of the EBV latent membrane protein 1 (LMP1). LMP1 trafficking and signaling require its incorporation into membrane rafts. Conversely, raft environment is likely to modulate LMP1 activity. In order to investigate NPC-specific raft partners of LMP1, rafts derived from the C15 NPC xenograft were submitted to preparative immunoprecipitation of LMP1 combined with mass spectrometry analysis of coimmunoprecipitated proteins. Through this procedure, galectin 9, a beta-galactoside binding lectin and Hodgkin tumor antigen, was identified as a novel LMP1 partner. LMP1 interaction with galectin 9 was confirmed by coimmunoprecipitation and Western blotting in whole-cell extracts of NPC and EBV-transformed B cells (lymphoblastoid cell lines [LCLs]). Using mutant proteins expressed in HeLa cells, LMP1 was shown to bind galectin 9 in a TRAF3-independent manner. Galectin 9 is abundant in NPC biopsies as well as in LCLs, whereas it is absent in Burkitt lymphoma cells. In subsequent experiments, NPC cells were treated with Simvastatin, a drug reported to dissociate LMP1 from membrane rafts in EBV-transformed B cells. We found no significant effects of Simvastatin on the distribution of LMP1 and galectin 9 in NPC cell rafts. However, Simvastatin was highly cytotoxic for NPC cells, regardless of the presence or absence of LMP1. This suggests that Simvastatin is a potentially useful agent for the treatment of NPCs although it has distinct mechanisms of action in NPC and LCL cells.

* Corresponding author. Mailing address: Institut Gustave Roussy, CNRS UMR 8126, Villejuif Cedex 94805, France. Phone: 33 1 42 11 45 83. Fax: 33 1 42 11 54 94. E-mail: pbusson{at}igr.fr.

{dagger} C.P.-D. and C.K. contributed equally to this work.

Journal of Virology, November 2005, p. 13326-13337, Vol. 79, No. 21
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.21.13326-13337.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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