E4ORF3

E4ORF3 is a viral early protein encoded by the E4 region of the human adenovirus genome. It is produced early after infection and localizes to the nucleus, where it forms prominent track-like structures. E4ORF3 plays a role in counteracting host cellular defenses that would otherwise inhibit viral replication.

A key function of E4ORF3 is the rearrangement of cellular compartments known as PML nuclear bodies (PML-NBs). By reorganizing these structures and interacting with PML and Daxx, E4ORF3 disrupts antiviral signaling and chromatin-based restrictions that can impede viral gene expression and replication. This remodeling aids the establishment of efficient viral replication centers.

E4ORF3 operates in concert with other viral factors, notably E4ORF6, to form a functional E3 ubiquitin ligase complex. This complex targets host DNA damage response proteins, including components of the MRN complex, for proteasomal degradation. By dampening the DNA damage response, the virus creates a more favorable environment for viral DNA replication and genome maintenance.

Research on E4ORF3 provides insight into adenovirus biology and broader virus-host interactions, particularly how viruses modulate intrinsic immunity and the DNA damage response. The protein’s activity in reorganizing PML-NBs and antagonizing DDR signaling is a focal point for understanding viral replication strategies and host defense mechanisms.