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Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation.


ABSTRACT: Cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. As obligate pathogens, gammaherpesviruses have evolved a plethora of mechanisms to evade host immune responses. We have previously shown that murine gammaherpesvirus 68 (?HV68) induces the degradation of RelA, an essential subunit of the transcriptionally active NF-?B dimer, to evade cytokine production. Here, we report that the immediately early gene product of ?HV68, replication transactivator (RTA), functions as a ubiquitin E3 ligase to promote RelA degradation and abrogate cytokine production. A targeted genomic screen identified that RTA, out of 24 candidates, induces RelA degradation and abolishes NF-?B activation. Biochemical analyses indicated that RTA interacts with RelA and promotes RelA ubiquitination, thereby facilitating RelA degradation. Mutations within a conserved cysteine/histidine-rich, putative E3 ligase domain impaired the ability of RTA to induce RelA ubiquitination and degradation. Moreover, infection by recombinant ?HV68 carrying mutations that diminish the E3 ligase activity of RTA resulted in more robust NF-?B activation and cytokine induction than did infection by wild-type ?HV68. These findings support the conclusion that ?HV68 subverts early NF-?B activation and cytokine production through RTA-induced RelA degradation, uncovering a key function of RTA that antagonizes the intrinsic cytokine production during gammaherpesvirus infection.

SUBMITTER: Dong X 

PROVIDER: S-EPMC3302405 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation.

Dong Xiaonan X   He Zhiheng Z   Durakoglugil Deniz D   Arneson Lisa L   Shen Yan Y   Feng Pinghui P  

Journal of virology 20111130 4


Cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. As obligate pathogens, gammaherpesviruses have evolved a plethora of mechanisms to evade host immune responses. We have previously shown that murine gammaherpesvirus 68 (γHV68) induces the degradation of RelA, an essential subunit of the transcriptionally active NF-κB dimer, to evade cytokine production. Here, we report that the immediately early gene product of γHV68, replication transactivator (  ...[more]

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