Termination of NF-κB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase

• Lénia Rodrigues ^[1] ; Josina Filipe ^[1] ; Mark P Seldon ^[2] ; Lidia Fonseca ^[1] ; Josef Anrather ^[3] ; Miguel P Soares ^[2] ; J Pedro Simas ^[1]
  1. [1] Universidade de Lisboa

     Universidade de Lisboa

     Socorro, Portugal

     
  2. [2] Instituto Gulbenkian de Ciência

     Instituto Gulbenkian de Ciência

     Oeiras e São Julião da Barra, Portugal

     
  3. [3] Cornell University

     Cornell University

     City of Ithaca, Estados Unidos

     

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 28, Nº. 9, 2009, págs. 1283-1295
• Idioma: inglés
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  • 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-κB) transcriptional activity through poly-ubiquitination and subsequent proteasomal-dependent nuclear degradation of the NF-κB 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-κB 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-κB 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-κB as a regulatory mechanism of this signalling pathway.