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Originally published In Press as doi:10.1074/jbc.M005461200 on October 12, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1195-1203, January 12, 2001
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Mechanism of Action of a Novel Latent Membrane Protein-1 Dominant Negative*

Paul BrennanDagger , J. Eike Floettmann§, Anja Mehl, Matthew Jones, and Martin Rowe

From the Department of Medicine, Tenovus Building, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XX, United Kingdom

Latent membrane protein-1 (LMP1) is a signaling molecule expressed by Epstein-Barr virus during latency. LMP1 is essential for B-cell immortalization by Epstein-Barr virus and transforms rodent fibroblasts. It activates many distinct signaling pathways including the transcription factors NFkappa B and AP1. We have generated a mutant of LMP1 with four point mutations; amino acids 204, 206, and 208 were mutated to alanine, and amino acid 384 was mutated to glycine. This mutant, termed LMP1AAAG, is not only unable to activate nuclear signaling pathways, but also inhibits signaling from wild type LMP1. We have demonstrated the effectiveness, selectivity, and mechanism of this inhibitory molecule. It inhibits LMP1-stimulated NFkappa B, STAT, and Jun transcriptional activity. It is selective, as it does not inhibit TNF or interleukin-2 signaling. We have demonstrated that it does not sequester the downstream signaling molecule, TRAF2, but instead binds LMP1 and interferes with its ability to bind TRAF2. This demonstrates the importance of the interplay between the signaling domains of LMP1 and the oligomeric structure of LMP1 for effective signaling. It identifies a tool that will be useful to probe LMP1 function in disease.

* The work was supported by the Leukemia Research Fund, London, the Wellcome Trust, and European Biomed-2 Award BMH4-CT97-2567.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.

Dagger To whom correspondence should be addressed. Tel.: 44-29-20744517; Fax: 44-29-20745003; E-mail: brennanp@cardiff.ac.uk.

§ Present address: Dept. of Molecular Biology, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH United Kingdom.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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