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, Sarah R. Osvath, Xiao Ming Xu, Grace Li, Francis K.M. Chan, John W. Barrett, Douglas McFadden

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The poxvirus tumor necrosis factor receptor (TNFR) homologue T2 has immunomodulatory properties; secreted myxoma virus T2 (M-T2) protein binds and inhibits rabbit TNF-α, 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-α, 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-α-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-α 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-α/TNFR therapeutics.

Original languageEnglish (US)
Pages (from-to)9300-9309
Number of pages10
JournalJournal of Virology
Volume80
Issue number18
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

Fingerprint

Myxoma virus
Poxviridae
Receptors, Tumor Necrosis Factor, Type I
tumor necrosis factors
Tumor Necrosis Factor Receptors
cell death
Virus Assembly
Cell Death
receptors
Proteins
proteins
death
apoptosis
TNF-Related Apoptosis-Inducing Ligand Receptors
Jurkat Cells
cycloheximide
Etoposide
Cycloheximide
lymphocytes
irradiation

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. / Sedger, Lisa M.; Osvath, Sarah R.; Xu, Xiao Ming; Li, Grace; Chan, Francis K.M.; Barrett, John W.; McFadden, Douglas.

In: Journal of Virology, Vol. 80, No. 18, 01.09.2006, p. 9300-9309.

Research output: Contribution to journalArticle

Sedger, Lisa M. ; Osvath, Sarah R. ; Xu, Xiao Ming ; Li, Grace ; Chan, Francis K.M. ; Barrett, John W. ; McFadden, Douglas. / Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death. In: Journal of Virology. 2006 ; Vol. 80, No. 18. pp. 9300-9309.
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