Murine gamma herpesvirus 68 hijacks MAVS and IKK? to abrogate NF?B activation and antiviral cytokine production.

ABSTRACT: Upon viral infection, mitochondrial antiviral signaling (MAVS) protein serves as a key adaptor to promote cytokine production. We report here that murine gamma herpesvirus 68 (?HV68), a model virus for oncogenic human gamma herpesviruses, subverts cytokine production via the MAVS adaptor. During early infection, ?HV68 hijacks MAVS and IKK? to induce the site-specific phosphorylation of RelA, a crucial subunit of the transcriptionally active NF?B dimer, which primes RelA for the proteasome-mediated degradation. As such, ?HV68 efficiently abrogated NF?B activation and cytokine gene expression. Conversely, uncoupling RelA degradation from ?HV68 infection promoted NF?B activation and elevated cytokine production. Loss of MAVS increased cytokine production and immune cell infiltration in the lungs of ?HV68-infected mice. Moreover, exogenous expression of the phosphorylation- and degradation-resistant RelA variant restored ?HV68-induced cytokine production. Our findings uncover an intricate strategy whereby signaling via the upstream MAVS adaptor is intercepted by a pathogen to nullify the immediate downstream effector, RelA, of the innate immune pathway.

SUBMITTER: Dong X 

PROVIDER: S-EPMC3213086 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature