Murine Gammaherpesvirus 68 Evades Host Cytokine Production via Replication Transactivator-Induced RelA Degradation

Cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. As obligate pathogens, gam-maherpesviruses have evolved a plethora of mechanisms to evade host immune responses. We have previously shown that mu-rine 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 transactiva-tor (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. Biochemi-cal 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 gammaherpesvi-rus infection. Gammaherpesviruses are a group of large DNA viruses thatpersist within their hosts for life, after primary infection. Members of the subfamily Gammaherpesvirinae include Kaposi’