Abstract
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)α and IFNγ, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNγ-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.
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References
Adachi K, Ichinose T, Takizawa N, Watanabe K, Kitazato K, Kobayashi N . (2007). Inhibition of betanodavirus infection by inhibitors of endosomal acidification. Arch Virol 152: 2217–2224.
Allen MD, Young LS, Dawson CW . (2005). The Epstein–Barr virus-encoded LMP2A and LMP2B proteins promote epithelial cell spreading and motility. J Virol 79: 1789–1802.
Anderson LJ, Longnecker R . (2008a). An auto-regulatory loop for EBV LMP2A involves activation of Notch. Virology 371: 257–266.
Anderson LJ, Longnecker R . (2008b). Epstein Barr virus latent membrane protein 2A exploits Notch1 to alter B cell identity in vivo. Blood 113: 108–116.
Beadling C, Ng J, Babbage JW, Cantrell DA . (1996). Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J 15: 1902–1913.
Cassady KA, Gross M . (2002). The herpes simplex virus type 1 U(S)11 protein interacts with protein kinase R in infected cells and requires a 30-amino-acid sequence adjacent to a kinase substrate domain. J Virol 76: 2029–2035.
Cho NH, Kingston D, Chang H, Kwon EK, Kim JM, Lee JH et al. (2006). Association of herpesvirus saimiri tip with lipid raft is essential for downregulation of T-cell receptor and CD4 coreceptor. J Virol 80: 108–118.
Claudinon J, Monier MN, Lamaze C . (2007). Interfering with interferon receptor sorting and trafficking: impact on signalling. Biochimie 89: 735–743.
Conrad M, Bubb VJ, Schlegel R . (1993). The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein. J Virol 67: 6170–6178.
Dawson CW, Eliopoulos AG, Blake SM, Barker R, Young LS . (2000). Identification of functional differences between prototype Epstein–Barr virus-encoded LMP1 and a nasopharyngeal carcinoma-derived LMP1 in human epithelial cells. Virology 272: 204–217.
Dawson CW, George JH, Blake SM, Longnecker R, Young LS . (2001). The Epstein-Barr virus encoded latent membrane protein 2A augments signaling from latent membrane protein 1. Virology 289: 192–207.
Dykstra ML, Longnecker R, Pierce SK . (2001). Epstein–Barr virus coopts lipid rafts to block the signalling and antigen transport functions of the BCR. Immunity 14: 57–67.
Ikeda M, Longnecker R . (2007). Cholesterol is critical for Epstein–Barr virus latent membrane protein 2A trafficking and protein stability. Virology 360: 461–468.
Katze MG . (2002). Interferon, PKR, virology, and genomics: what is past and what is next in the new millennium? J Interferon Cytokine Res 22: 283–286.
Li Q, Means R, Lang S, Jung JU . (2007). Downregulation of gamma interferon receptor 1 by Kaposi's sarcoma-associated herpesvirus K3 and K5. J Virol 81: 2117–2127.
Liu J, Plotnikov A, Banerjee A, Suresh Kumar KG, Ragimbeau J, Marijanovic Z et al. (2008). Ligand-independent pathway that controls stability of interferon alpha receptor. Biochem Biophys Res Commun 367: 388–393.
Longan L, Longnecker R . (2000). Epstein–Barr virus latent membrane protein 2A has no growth-altering effects when expressed in differentiating epithelia. J Gen Virol 81: 2245–2252.
Longnecker R . (2000). Epstein–Barr virus latency: LMP2, a regulator or means for Epstein–Barr virus persistence? Adv Cancer Res 79: 175–200.
Mancao C, Hammerschmidt W . (2007). Epstein–Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110: 3715–3721.
Morrison JA, Klingelhutz AJ, Raab-Traub N . (2003). Epstein–Barr virus latent membrane protein 2A activates β-catenin signalling in epithelial cells. J Virol 77: 12276–12284.
Morrison TE, Mauser A, Wong A, Ting JP, Kenney SC . (2001). Inhibition of IFN-gamma signalling by an Epstein–Barr virus immediate-early protein. Immunity 15: 787–799.
Nanbo A, Takada K . (2002). The role of Epstein–Barr virus-encoded small RNAs (EBERs) in oncogenesis. Rev Med Virol 12: 321–326.
Offermann MK . (2007). Kaposi sarcoma herpesvirus-encoded interferon regulator factors. Curr Top Microbiol Immunol 312: 185–209.
Ogino T, Moriai S, Ishida Y, Ishii H, Katayama A, Miyokawa N et al. (2007). Association of immunoescape mechanisms with Epstein–Barr virus infection in nasopharyngeal carcinoma. Int J Cancer 120: 2401–2410.
Raab-Traub N . (2002). Epstein–Barr virus in the pathogenesis of NPC. Semin Cancer Biol 12: 431–441.
Ragimbeau J, Dondi E, Alcover A, Eid P, Uze G, Pellegrini S . (2003). The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J 22: 537–547.
Randall RE, Goodbourn S . (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89: 1–47.
Rechsteiner MP, Berger C, Weber M, Sigrist JA, Nadal D, Bernasconi M . (2007). Silencing of latent membrane protein 2B reduces susceptibility to activation of lytic Epstein–Barr virus in Burkitt's lymphoma Akata cells. J Gen Virol 88: 1454–1459.
Rechsteiner MP, Berger C, Zauner L, Sigrist JA, Weber M, Longnecker R et al. (2008). Latent membrane protein 2B regulates susceptibility to induction of lytic Epstein–Barr virus infection. J Virol 82: 1739–1747.
Rezaee SA, Cunningham C, Davison AJ, Blackbourn DJ . (2006). Kaposi's sarcoma-associated herpesvirus immune modulation: an overview. J Gen Virol 87: 1781–1804.
Rovedo M, Longnecker R . (2007). Epstein–Barr virus latent membrane protein 2B (LMP2B) modulates LMP2A activity. J Virol 81: 84–94.
Scholle F, Bendt KM, Raab-Traub N . (2000). Epstein–Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J Virol 74: 10681–10689.
Stewart S, Dawson CW, Takada K, Curnow J, Moody CA, Sixbey JW et al. (2004). Epstein–Barr virus-encoded LMP2A regulates viral and cellular gene expression by modulation of the NF-kappaB transcription factor pathway. Proc Natl Acad Sci USA 101: 15730–15735.
Tao Q, Chan AT . (2007). Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. Expert Rev Mol Med 9: 1–24.
Uozaki H, Fukayama M . (2008). Epstein–Barr virus and gastric carcinoma—viral carcinogenesis through epigenetic mechanisms. Int J Clin Exp Pathol 1: 198–216.
Young LS, Rickinson AB . (2004). Epstein–Barr virus: 40 years on. Nat Rev Cancer 4: 757–768.
Acknowledgements
This work was supported by programme funding from Cancer Research UK and the European Commission's FP6 Life Sciences Health Programme (INCA project LSHC-CT-.2005-018704).
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Shah, K., Stewart, S., Wei, W. et al. The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation. Oncogene 28, 3903–3914 (2009). https://doi.org/10.1038/onc.2009.249
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DOI: https://doi.org/10.1038/onc.2009.249
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