ABSTRACT The oncogenic Epstein–Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) constitutively activates the ‘canonical’ NF-_κ_B pathway that involves the phosphorylation

and degradation of I_κ_B_α_ downstream of the I_κ_B kinases (IKKs). In this study, we show that LMP1 also promotes the proteasome-mediated proteolysis of p100 NF-_κ_B2 resulting in the

generation of active p52, which translocates to the nucleus in complex with the p65 and RelB NF-_κ_B subunits. LMP1-induced NF-_κ_B transactivation is reduced in nf-kb2−/− mouse embryo

fibroblasts, suggesting that p100 processing contributes to LMP1-mediated NF-_κ_B transcriptional effects. This pathway is likely to operate _in vivo_, as the expression of LMP1 in primary

p65, occurs in the absence of IKK_γ_. These data point to the existence of a novel signalling pathway that regulates NF-_κ_B in LMP1-expressing cells, and may thereby play a role in both

oncogenic transformation and the establishment of persistent EBV infection. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn more Buy this

article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in

* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS EPSTEIN-BARR VIRUS-DRIVEN B CELL LYMPHOMA MEDIATED BY A DIRECT

LMP1-TRAF6 COMPLEX Article Open access 10 January 2024 THE NUCLEIC ACID BINDING PROTEIN SFPQ REPRESSES EBV LYTIC REACTIVATION BY PROMOTING HISTONE H1 EXPRESSION Article Open access 16 May

2024 HIPPO SIGNALING PATHWAY REGULATES EBOLA VIRUS TRANSCRIPTION AND EGRESS Article Open access 13 August 2024 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. Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

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 * MRC Centre for Immune Regulation, The University of Birmingham Medical School, Birmingham, B15 2TA, UK Aristides G Eliopoulos, Jorge H Caamano & Lawrence S Young

* Department of Pathology, The University of Birmingham Medical School, Birmingham, B15 2TA, UK Joanne Flavell, Gary M Reynolds & Paul G Murray * INSERM U532, Institut de Recherche sur

la Peau, Hopital Saint-Louis, Paris, Cedex 10, 75475, France Jean-Luc Poyet Authors * Aristides G Eliopoulos View author publications You can also search for this author inPubMed Google

Scholar * Jorge H Caamano View author publications You can also search for this author inPubMed Google Scholar * Joanne Flavell View author publications You can also search for this author

inPubMed Google Scholar * Gary M Reynolds View author publications You can also search for this author inPubMed Google Scholar * Paul G Murray View author publications You can also search

for this author inPubMed Google Scholar * Jean-Luc Poyet View author publications You can also search for this author inPubMed Google Scholar * Lawrence S Young View author publications You

can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Aristides G Eliopoulos. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE Eliopoulos, A., Caamano, J., Flavell, J. _et al._ Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-_κ_B2 to p52 via an

IKK_γ_/NEMO-independent signalling pathway. _Oncogene_ 22, 7557–7569 (2003). https://doi.org/10.1038/sj.onc.1207120 Download citation * Received: 22 July 2003 * Accepted: 14 August 2003 *

Published: 23 October 2003 * Issue Date: 23 October 2003 * DOI: https://doi.org/10.1038/sj.onc.1207120 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

KEYWORDS * LMP1 * EBV * NF-_κ_B2 * signalling