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Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway

Oncogene volume 22, pages 7557–7569 (2003)Cite this article

Abstract

The oncogenic Epstein–Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the ‘canonical’ NF-κB pathway that involves the phosphorylation and degradation of IκBα downstream of the IκB kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-κB2 resulting in the generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-κB subunits. LMP1-induced NF-κB transactivation is reduced in nf-kb2−/− mouse embryo fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-κB transcriptional effects. This pathway is likely to operate in vivo, as the expression of LMP1 in primary EBV-positive Hodgkin's lymphoma and nasopharyngeal carcinoma biopsies correlates with the nuclear accumulation of p52. Interestingly, while the ability of LMP1 to activate the canonical NF-κB pathway is impaired in cells lacking IKKγ/NEMO, the regulatory subunit of the IKK complex, p100 processing remains unaffected. As a result, nuclear translocation of p52, but not p65, occurs in the absence of IKKγ. These data point to the existence of a novel signalling pathway that regulates NF-κB in LMP1-expressing cells, and may thereby play a role in both oncogenic transformation and the establishment of persistent EBV infection.

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References

  • Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A and Pestell RG . (1995). J. Biol. Chem., 270, 23589–23597.

  • Caamano JH, Perez P, Lira SA and Bravo R . (1996). Mol. Cell. Biol., 16, 1342–1348.

  • Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C, Snapper CM and Bravo R . (1998). J. Exp. Med., 187, 185–196.

  • Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J and Kieff E . (2000). Proc. Natl. Acad. Sci. USA, 97, 6055–6060.

  • Cahir-McFarland ED, Izumi KM and Mosialos G . (1999). Oncogene, 18, 6959–6964.

  • Claudio E, Brown K, Park S, Wang H and Siebenlist U . (2002). Nat. Immunol., 3, 958–965.

  • Cogswell PC, Guttridge DC, Funkhouser WK and Baldwin Jr AS . (2000). Oncogene, 19, 1123–1131.

  • Coope HJ, Atkinson PG, Huhse B, Belich M, Janzen J, Holman MJ, Klaus GG, Johnston LH and Ley SC . (2002). EMBO J., 21, 5375–5385.

  • Damania B, Choi JK and Jung JU . (2000). J. Virol., 74, 1593–1601.

  • Dawson CW, Tramountanis G, Eliopoulos AG and Young LS . (2003). J. Biol. Chem., 278, 3694–3704.

  • Dejardin E, Droin NM, Delhase M, Haas E, Cao Y, Makris C, Li ZW, Karin M, Ware CF and Green DR . (2002). Immunity, 17, 525–535.

  • Eliopoulos AG, Davies C, Blake SS, Murray P, Najafipour S, Tsichlis PN and Young LS . (2002a). J. Virol., 76, 4567–4579.

  • Eliopoulos AG, Dumitru CD, Wang C-C, Cho J and Tsichlis PN . (2002b). EMBO J., 21, 4831–4840.

  • Eliopoulos AG, Gallagher NJ, Blake SMS, Dawson CW and Young LS . (1999). J. Biol. Chem., 274, 16085–16096.

  • Eliopoulos AG, Waites ER, Blake SM, Davies C, Murray P and Young LS . (2003). J. Virol., 77, 1316–1328.

  • Eliopoulos AG and Young LS . (2001). Semin. Cancer Biol., 11, 435–444.

  • Flavell JR, Baumforth KR, Williams DM, Lukesova M, Madarova J, Noskova V, Prochazkova J, Lowe D, Kolar Z, Murray PG and Nelson PN . (2000). Mol. Pathol., 53, 145–149.

  • Floettmann JE and Rowe M . (1997). Oncogene, 15, 1851–1858.

  • Franzoso G, Carlson L, Poljak L, Shores EW, Epstein S, Leonardi A, Grinberg A, Tran T, Scharton-Kersten T, Anver M, Love P, Brown K and Siebenlist U . (1998). J. Exp. Med., 187, 147–159.

  • Fries KL, Miller WE and Raab-Traub N . (1996). J. Virol., 70, 8653–8659.

  • Garceau N, Kosaka Y, Masters S, Hambor J, Shinkura R, Honjo T and Noelle RJ . (2000). J. Exp. Med., 191, 381–385.

  • Ghosh S and Karin M . (2002). Cell, 109 (Suppl), S81–S96.

  • Gires O, Zimber-Strobl U, Gonella R, Ueffing M, Marschall G, Zeidler R, Pich D and Hammerschmidt W . (1997). EMBO J., 16, 6131–6140.

  • Huen DS, Henderson SA, Croom-Carter D and Rowe M . (1995). Oncogene, 10, 549–560.

  • He Z, Xin B, Yang X, Chan C and Cao L . (2000). Cancer Res., 60, 1845–1848.

  • Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E and Rickinson AB . (1991). Cell, 65, 1107–1115.

  • Herrero JA, Mathew P and Paya CV . (1995). J. Virol., 69, 2168–2174.

  • Ishikawa H, Carrasco D, Claudio E, Ryseck RP and Bravo R . (1997). J. Exp. Med., 186, 999–1014.

  • Izumi KM and Kieff ED . (1997). Proc. Natl. Acad. Sci. USA, 94, 12592–12597.

  • Izumi KM, McFarland EC, Ting AT, Riley E, Seed B and Kieff ED . (1999). Mol. Cell. Biol., 19, 5759–5767.

  • Kaisho T, Takeda K, Tsujimura T, Kawai T, Nomura F, Terada N and Akira S . (2001). J. Exp. Med., 193, 417–426.

  • Kanno T, Franzoso G and Siebenlist U . (1994). Proc. Natl. Acad. Sci. USA, 91, 12634–12638.

  • Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T and Kikutani H . (1994). Immunity, 1, 167–178.

  • Kaye KM, Izumi KM and Kieff E . (1993). Proc. Natl. Acad. Sci. USA, 90, 9150–9154.

  • Kaye KM, Izumi KM, Mosialos G and Kieff E . (1995). J. Virol., 69, 675–683.

  • Koike R, Nishimura T, Yasumizu R, Tanaka H, Hataba Y, Watanabe T, Miyawaki S and Miyasaka M . (1996). Eur. J. Immunol., 26, 669–675.

  • Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V and Raab-Traub N . (1998). Proc. Natl. Acad. Sci. USA, 95, 11963–11968.

  • Lam N and Sugden B . (2003). EMBO J., 22, 3027–3038.

  • Lamarche N, Tapon N, Stowers L, Burbelo PD, Aspenstrom P, Bridges T, Chant J and Hall A . (1996). Cell, 87, 519–529.

  • Lin X, Mu Y, Cunningham Jr ET, Marcu KB, Geleziunas R and Greene WC . (1998). Mol. Cell. Biol., 18, 5899–5907.

  • Ling L, Cao Z and Goeddel DV . (1998). Proc. Natl. Acad. Sci. USA, 95, 3792–3797.

  • Luftig MA, Cahir-McFarland E, Mosialos G and Kieff E . (2001). J. Biol. Chem., 276, 14602–14606.

  • Malinin NL, Boldin MP, Kovalenko AV and Wallach D . (1997). Nature (London), 385, 540–544.

  • Matsumoto M, Mariathasan S, Nahm MH, Baranyay F, Peschon JJ and Chaplin DD . (1996). Science, 271, 1289–1291.

  • Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, Takeda K, Akira S and Matsumoto M . (2001). J. Exp. Med., 193, 631–636.

  • Mordmuller B, Krappmann D, Esen M, Wegener E and Scheidereit C . (2003). EMBO Rep., 4, 82–87.

  • Murono S, Inoue H, Tanabe T, Joab I, Yoshizaki T, Furukawa M and Pagano JS . (2001). Proc. Natl. Acad. Sci. USA, 98, 6905–6910.

  • Nolan GP, Fujita T, Bhatia K, Huppi C, Liou HC, Scott ML and Baltimore D . (1993). Mol. Cell. Biol., 13, 3557–3566.

  • Paine E, Scheinam RI, Baldwin AS and Raab-Traub N . (1995). J. Virol., 69, 4572–4576.

  • Perkins ND . (1997). Int. J. Biochem. Cell Biol., 29, 1433–1448.

  • Poyet JL, Srinivasula SM and Alnemri ES . (2001). J. Biol. Chem., 276, 3183–3187.

  • Rayet B and Gelinas C . (1999). Oncogene, 18, 6938–6947.

  • Rickinson AB and Kieff E . (1996). Virology. Knipe M and Howley PM (eds). Raven Press: New York, pp. 2397–2446.

    Google Scholar 

  • Rocha S, Martin AM, Meek DW and Perkins ND . (2003). Mol. Cell. Biol., 23, 4713–4727.

  • Rothwarf DM, Zandi E, Natoli G and Karin M . (1998). Nature, 395, 297–300.

  • Rowe M, Evans HS, Young LS, Hennessy K, Kieff E and Rickinson AB . (1987). J. Gen. Virol., 68, 1575–1586.

  • Santoro MG, Rossi A and Amici C . (2003). EMBO J., 22, 2552–2560.

  • Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E and Scott ML . (2001). Science, 293, 2111–2114.

  • Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC and Karin M . (2001). Science, 293, 1495–1499.

  • Solan NJ, Miyoshi H, Carmona EM, Bren GD and Paya CV . (2002). J. Biol. Chem., 277, 1405–1418.

  • Sylla BS, Hung SC, Davidson DM, Hatzivassiliou E, Malinin NL, Wallach D, Gilmore TD, Kieff E and Mosialos G . (1998). Proc. Natl. Acad. Sci. USA, 95, 10106–10111.

  • Viatour P, Bentires-Alj M, Chariot A, Deregowski V, de Leval L, Merville MP and Bours V . (2003). Leukemia, 17, 1349–1356.

  • Wang Y, Cui H, Schroering A, Ding JL, Lane WS, McGill G, Fisher DE and Ding HF . (2002). Nat. Cell Biol., 4, 888–893.

  • Westerheide SD, Mayo MW, Anest V, Hanson JL and Baldwin Jr AS . (2001). Mol. Cell. Biol., 21, 8428–8436.

  • Wilson JB, Weinberg W, Johnson R, Yuspa S and Levine AJ . (1990). Cell, 61, 1315–1327.

  • Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M and Sun SC . (2001a). EMBO J., 20, 6805–6815.

  • Xiao G, Harhaj EW and Sun SC . (2001b). Mol. Cell, 7, 401–409.

  • Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ and Israel A . (1998). Cell, 93, 1231–1240.

  • Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV and Schreiber RD . (2001). Science, 291, 2162–2165.

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Acknowledgements

We are grateful to C Dawson, H Huang, J Inoue, E Kieff, L Laverick, N Perkins, M Rowe, K Ryan, G Tsao, S Yamaoka and D Wallach for providing us with reagents, and to Liz Hodgkins for technical assistance. This work was supported by a Medical Research Council (MRC, UK) Career Development Award to AGE and by a Cancer Research UK Grant (SP2584) to AGE and LSY.

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Authors and Affiliations

  1. Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Aristides G Eliopoulos, Joanne Flavell, Gary M Reynolds, Paul G Murray & Lawrence S Young

  2. MRC Centre for Immune Regulation, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Aristides G Eliopoulos, Jorge H Caamano & Lawrence S Young

  3. Department of Pathology, The University of Birmingham Medical School, Birmingham, B15 2TA, UK

    Joanne Flavell, Gary M Reynolds & Paul G Murray

  4. INSERM U532, Institut de Recherche sur la Peau, Hopital Saint-Louis, Paris, Cedex 10, 75475, France

    Jean-Luc Poyet

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Correspondence to Aristides G Eliopoulos.

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Eliopoulos, A., Caamano, J., Flavell, J. et al. Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway. Oncogene 22, 7557–7569 (2003). https://doi.org/10.1038/sj.onc.1207120

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