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Journal of Virology, March 2003, p. 3749-3758, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3749-3758.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transmembrane Domains 1 and 2 of the Latent Membrane Protein 1 of Epstein-Barr Virus Contain a Lipid Raft Targeting Signal and Play a Critical Role in Cytostasis

William F. Coffin III, Timothy R. Geiger, and Jennifer M. Martin*

Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309

Received 3 October 2002/ Accepted 23 December 2002

The latent membrane protein 1 (LMP-1) oncoprotein of Epstein-Barr virus (EBV) is a constitutively active, CD40-like cell surface signaling protein essential for EBV-mediated human B-cell immortalization. Like ligand-activated CD40, LMP-1 activates NF-{kappa}B and Jun kinase signaling pathways via binding, as a constitutive oligomer, to tumor necrosis factor receptor-associated factors (TRAFs). LMP-1's lipid raft association and oligomerization have been linked to its activation of cell signaling pathways. Both oligomerization and lipid raft association require the function of LMP-1's polytopic multispanning transmembrane domain, a domain that is indispensable for LMP-1's growth-regulatory signaling activities. We have begun to address the sequence requirements of the polytopic hydrophobic transmembrane domain for LMP-1's signaling and biochemical activities. Here we report that transmembrane domains 1 and 2 are sufficient for LMP-1's lipid raft association and cytostatic activity. Transmembrane domains 1 and 2 support NF-{kappa}B activation, albeit less potently than does the entire polytopic transmembrane domain. Interestingly, LMP-1's first two transmembrane domains are not sufficient for oligomerization or TRAF binding. These results suggest that lipid raft association and oligomerization are mediated by distinct and separable activities of LMP-1's polytopic transmembrane domain. Additionally, lipid raft association, mediated by transmembrane domains 1 and 2, plays a significant role in LMP-1 activation, and LMP-1 can activate NF-{kappa}B via an oligomerization/TRAF binding-independent mechanism. To our knowledge, this is the first demonstration of an activity's being linked to individual membrane-spanning domains within LMP-1's polytopic transmembrane domain.

* Corresponding author. Mailing address: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Campus Box 347, Boulder, CO 80309. Phone: (303) 492-6346. Fax: (303) 492-1587. E-mail: jm{at}colorado.edu.

Journal of Virology, March 2003, p. 3749-3758, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3749-3758.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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