Vaccinia virus E3 protein (E3)

The Vaccinia virus E3 protein, encoded by the E3L gene, is a multifunctional immune evasion factor and a critical virulence determinant in poxviruses (UniProt Q86638). It consists of two primary domains: an N-terminal Z-DNA binding domain (ZBD) and a C-terminal double-stranded RNA binding domain (dsRBD) (PubMed: 11290764). E3 functions primarily by sequestering viral dsRNA and Z-RNA, thereby preventing the activation of host innate immune sensors such as protein kinase R (PKR), 2'-5' oligoadenylate synthetase (OAS), and Z-DNA binding protein 1 (ZBP1) (PubMed: 28100618). By inhibiting these pathways, E3 effectively blocks the induction of the interferon response, prevents the shutdown of protein synthesis, and suppresses necroptotic cell death (PubMed: 32024034). Additionally, E3 interacts directly with host factors like ISG15 and IRF3 to further dampen the antiviral state (PubMed: 18483451). Due to its essential role in viral replication and host range, E3 is a prominent target for the development of novel antiviral therapeutics against orthopoxviruses, including variola virus and monkeypox virus (PubMed: 20519457). While no E3-specific inhibitors are currently FDA-approved, research into small molecules that disrupt its RNA-binding or protein-protein interaction surfaces is ongoing.

Other names

E3L proteinRNA-binding protein OPG065p25p20dsRNA-binding proteinZ-DNA binding proteinInterferon resistance protein

Sequestration of double-stranded RNA (dsRNA) and Z-form RNA (Z-RNA) to prevent host pattern recognition receptor (PRR) activation; direct protein-protein interaction with host antiviral factors like PKR and ISG15.