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  • The EMBO Journal (2009) 28, 1283 - 1295
  • doi:10.1038/emboj.2009.74

Published online: 26 March 2009

Termination of NF-kappaB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligaseEMBO Open

Lénia Rodrigues1,2, Josina Filipe1,2, Mark P Seldon2, Lidia Fonseca1,2, Josef Anrather3, Miguel P Soares2 and J Pedro Simas1,2

  1. Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
  3. Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA

Correspondence to:

J Pedro Simas, Instituto de Microbiologia e Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal. Tel.: +351 217 999 458; Fax: +351 217 999 459; E-mail: psimas@fm.ul.pt

Received 16 September 2008; Accepted 3 March 2009

Host colonisation by lymphotropic gammaherpesviruses depends critically on the expansion of viral genomes in germinal centre (GC) B cells. Yet, host and virus molecular mechanisms involved in driving such proliferation remain largely unknown. Here, we show that the ORF73 protein encoded by the murid herpesvirus-4 (MuHV-4) inhibits host nuclear factor-kappa B (NF-kappaB) transcriptional activity through poly-ubiquitination and subsequent proteasomal-dependent nuclear degradation of the NF-kappaB family member p65/RelA. The mechanism involves the assembly of an ElonginC/Cullin5/SOCS (suppressors of cytokine signalling)-like complex, mediated by an unconventional viral SOCS-box motif present in ORF73. Functional deletion of this SOCS-box motif ablated NF-kappaB inhibitory effect of ORF73, suppressed MuHV-4 expansion in GC B cells and prevented MuHV-4 persistent infection in mice. These findings demonstrate that viral inhibition of NF-kappaB activity in latently infected GC centroblasts is critical for the establishment of a gammaherpesvirus persistent infection, underscoring the physiological importance of proteasomal degradation of RelA/NF-kappaB as a regulatory mechanism of this signalling pathway.

  • Keywords:

    • ECS ubiquitin-ligase,
    • gammaherpesvirus,
    • germinal centre latency,
    • NF-kappaB,
    • SOCS

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The EMBO Journal is published by Nature Publishing Group on behalf of European Molecular Biology Organization