Distinct domains of M-T2, the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition.
The myxoma virus tumor necrosis factor (TNF) receptor homolog, M-T2, is expressed both as a secreted glycoprotein that inhibits the cytolytic activity of rabbit TNF-alpha and as an endoglycosidase H-sensitive intracellular species that prevents myxoma virus-infected CD4+ T lymphocytes from undergoing apoptosis. To compare the domains of M-T2 mediating extracellular TNF inhibition and intracellular apoptosis inhibition, recombinant myxoma viruses expressing nested C-terminal truncations of M-T2 protein were constructed. One mutant, deltaL113, containing intact copies of only two cysteine-rich domains, was not secreted and was incapable of binding rabbit TNF-alpha yet retained full ability to inhibit virus-induced apoptosis of RL-5 cells. Thus, the minimal domain of intracellular M-T2 protein required to inhibit apoptosis is distinct from that required by the extracellular M-T2 for functional TNF-alpha binding and inhibition. This is the first report of a virus-encoded immunomodular protein with two distinct antiimmune properties.
Schreiber
M
M
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Sedger
L
L
McFadden
G
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites; D002460:Cell Line; D003545:Cysteine; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D007739:L Cells; D051379:Mice; D009233:Myxoma virus / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D006023:Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D003545:Cysteine