Interferon resistance protein E3 (E3L) (E3L)

The Vaccinia virus E3L protein is a potent bifunctional inhibitor of the host innate immune response, essential for poxvirus pathogenesis (UniProt P03263). It consists of an N-terminal Z-DNA/Z-RNA binding domain and a C-terminal double-stranded RNA (dsRNA) binding domain (PubMed: 11836341). The primary mechanism of E3L involves the sequestration of viral dsRNA, which prevents the activation of Protein Kinase R (PKR) and 2'-5'-oligoadenylate synthetase (OAS). This sequestration effectively stalls the host's ability to shut down protein synthesis and degrade viral RNA, allowing the virus to replicate (PubMed: 15650191). Additionally, E3L has been shown to inhibit necroptosis by targeting Z-DNA binding protein 1 (ZBP1), further protecting the virus from host-induced cell death (PubMed: 28179534). As a conserved protein across the Orthopoxvirus genus, E3L represents a strategic target for antiviral drug development, particularly for treating infections where current therapies like Tecovirimat may face resistance. Research into small molecule inhibitors targeting the dsRNA-binding pocket of E3L is ongoing to provide new countermeasures against emerging poxviral threats. While no drugs targeting E3L are currently FDA-approved, it remains a high-priority target in biodefense and virology research.

Other names

Vaccinia virus E3L proteindsRNA-binding protein E3p25 proteinE3Interferon resistance protein

E3L functions by sequestering double-stranded RNA (dsRNA) to prevent the activation of host innate immune sensors, thereby blocking the induction of the antiviral state.