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Journal of Virology, September 2006, p. 9300-9309, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.02449-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Poxvirus Tumor Necrosis Factor Receptor (TNFR)-Like T2 Proteins Contain a Conserved Preligand Assembly Domain That Inhibits Cellular TNFR1-Induced Cell Death

Lisa M. Sedger,1,2* Sarah R. Osvath,1 Xiao-Ming Xu,3 Grace Li,1 Francis K.-M. Chan,4 John W. Barrett,3 and Grant McFadden3

Institute for Immunology & Allergy Research and Centre for Virus Research, Westmead Millennium Institute, Department of Medicine, University of Sydney, Sydney, Australia,1 Department of Molecular Immunology, Immunex Corporation, Seattle, Washington,2 Department of Microbiology and Immunology, University of Western Ontario, and Robarts Research Institute, London, Ontario, Canada,3 Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts4

Received 22 November 2005/ Accepted 23 June 2006

The poxvirus tumor necrosis factor receptor (TNFR) homologue T2 has immunomodulatory properties; secreted myxoma virus T2 (M-T2) protein binds and inhibits rabbit TNF-{alpha}, while intracellular M-T2 blocks virus-induced lymphocyte apoptosis. Here, we define the antiapoptotic function as inhibition of TNFR-mediated death via a highly conserved viral preligand assembly domain (vPLAD). Jurkat cell lines constitutively expressing M-T2 were generated and shown to be resistant to UV irradiation-, etoposide-, and cycloheximide-induced death. These cells were also resistant to human TNF-{alpha}, but M-T2 expression did not alter surface expression levels of TNFRs. Previous studies indicated that T2's antiapoptotic function was conferred by the N-terminal region of the protein, and further examination of this region revealed a highly conserved N-terminal vPLAD, which is present in all poxvirus T2-like molecules. In cellular TNFRs and TNF-{alpha}-related apoptosis-inducing ligand (TRAIL) receptors (TRAILRs), PLAD controls receptor signaling competency prior to ligand binding. Here, we show that M-T2 potently inhibits TNFR1-induced death in a manner requiring the M-T2 vPLAD. Furthermore, we demonstrate that M-T2 physically associates with and colocalizes with human TNFRs but does not prevent human TNF-{alpha} binding to cellular receptors. Thus, M-T2 vPLAD is a species-nonspecific dominant-negative inhibitor of cellular TNFR1 function. Given that the PLAD is conserved in all known poxvirus T2-like molecules, we predict that it plays an important function in each of these proteins. Moreover, that the vPLAD confers an important antiapoptotic function confirms this domain as a potential target in the development of the next generation of TNF-{alpha}/TNFR therapeutics.

* Corresponding author. Mailing address: Westmead Millennium Institute, P.O. Box 412, Westmead, NSW 2145, Australia. Phone: 61-2-9845 7491. Fax: 61-2-9845 9100. E-mail: lisa_sedger{at}wmi.usyd.edu.au.

Journal of Virology, September 2006, p. 9300-9309, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.02449-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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