Adenovirus E4 ORF3 protein inhibits the interferon-mediated antiviral response

The PML oncogenic domain (POD/ND10/PML body) is a common target of DNA viruses, which replicate their genomes in proximity to this nuclear structure. The adenovirus early protein E4 ORF3 is both necessary and sufficient to rearrange PODs from punctate bodies into track-like structures. Although multiple hypotheses exist, the precise reason for this activity has not yet been elucidated. PML, the protein responsible for nucleating PODs, is an interferon (IFN)-stimulated gene, implicating the participation of this nuclear body in an innate antiviral response. Here, we demonstrate that E4 ORF3 is critical to the replicative success of adenovirus during the IFN-induced antiviral state. When cells are pretreated with either IFN-α or IFN-γ, a mutant virus that does not express E4 ORF3 is severely compromised for replication. This result suggests the functional significance of ORF3 track formation is the inhibition of a POD-mediated, antiviral mechanism. Replication of the E4 ORF3 mutant virus can be rescued following the introduction of E4 ORF3 from evolutionarily divergent adenoviruses, suggesting a conserved function for E4 ORF3 inhibition of the IFN-induced antiviral state. Furthermore, E4 ORF3 inhibition of an IFN-induced response is unrelated to the inhibition of adenovirus replication by the Mre11-Rad50-Nbs1 DNA repair complex. We propose that the evolutionarily conserved function of the adenovirus E4 ORF3 protein is the inhibition of a host interferon response to viral infection via disruption of the PML oncogenic domain.