Mechanism of measles virus failure to activate NF-kappaB in neuronal cells.
Lack of IFN-beta and MHC class I expression in measles virus (MV) infected neurons could impair the host antiviral defense mechanism and result in virus escape from recognition by cytotoxic T-cells. Induction of IFN-beta and MHC class I gene expression requires NF-kappaB activation which depends on degradation of IkappaBalpha, an inhibitory protein of NF-kappaB. In earlier studies we demonstrated that in contrast to glial cells, MV was unable to induce IkappaBalpha degradation in neuronal cells. It is unclear whether this failure is due to the presence of a neuron-specific IkappaBalpha isoform or a defect in the MV signaling cascade that leads to IkappaBalpha phosphorylation and degradation. In this study, an IkappaBalpha-wild type (WT) expression vector was transfected into neuronal and glial cells and subsequently exposed to MV. In contrast to glial cells, IkappaBalpha-WT was degraded in neuronal cells in response to TNFalpha but not MV. The findings eliminate the existence of an IkappaBalpha isoform in neuronal cells that is resistant to phosphorylation by MV. Blocking de novo protein synthesis with cyclohexamide had no effect on neuronal IkappaBalpha, indicating that lack of degradation rather than increased synthesis is responsible for IkappaBalpha accumulation in MV-stimulated neuronal cells. To determine if malfunction in the MV receptor CD46 is responsible for failure of IkappaBalpha phosphorylation and degradation, neuronal cells were transfected with a wild type CD46 (CD46-WT) expression vector. MV stimulation of CD46-WT transfected cells failed to induce IkappaBalpha degradation. Collectively these findings indicate that failure of MV to phosphorylate neuronal IkappaBalpha is not due to a presence of an IkappaBalpha isoform or malfunction of the MV receptor, and is more likely to be due to a defect in the signaling pathway that normally leads to IkappaBalpha phosphorylation and degradation.
Fang
Y Y
YY
Department of Neurology, University of Maryland at Baltimore, 21201, USA.
Song
Z M
ZM
Dhib-Jalbut
S
S
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D008459:Measles virus / Q000276:immunology / Q000378:metabolism*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000821:virology; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; C497857:CD46 protein, human; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha