The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation

Although frequently expressed in EBV-positive malignancies, the role that Latent membrane protein 2A and 2B (LMP2A, LMP2B) play in the oncogenic process remains obscure. Here we demonstrate 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 display decreased responsiveness to interferon (IFN)α and IFNγ, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to ISRE and GAS elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting “globally” on interferon-stimulated gene expression. Whilst 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 EBVs strategy to limit anti-viral responses and defines a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.