The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation.
Although frequently expressed in Epstein-Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)alpha and IFNgamma, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNgamma-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting 'globally' on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.
Shah
K M
KM
Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, Birmingham, UK.
Stewart
S E
SE
Wei
W
W
Woodman
C B J
CB
O'Neil
J D
JD
Dawson
C W
CW
Young
L S
LS
D002460:Cell Line; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000378:metabolism*; D017471:Receptors, Interferon / Q000276:immunology / Q000378:metabolism*; D020218:Response Elements / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D009856:Oncogene Proteins, Viral; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014763:Viral Matrix Proteins; D007371:Interferon-gamma