Disease relevance of E3L

• The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase [1].
• Compounds that block the Z-DNA-binding activity of E3L may also limit infection by the poxvirus [2].
• This finding may allow the design of a class of antiviral agents, including agents against variola (smallpox), which has an almost identical E3L [3].
• Here, we describe the crystal structure of the Zalpha domain from the E3L-like protein of Yaba-like disease virus, a Yatapoxvirus, in a complex with Z-DNA, solved at a 2.0-A resolution [4].
• Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis [5].

High impact information on E3L

• Here, we report that inhibition of hygromycin-B-induced apoptosis in HeLa cells depends on Z-DNA binding of the E3L Z alpha domain [6].
• Biological function of the vaccinia virus Z-DNA-binding protein E3L: gene transactivation and antiapoptotic activity in HeLa cells [6].
• A conserved feature of poxviruses is a protein, well characterized as E3L in vaccinia virus, that confers IFN resistance on the virus [4].
• Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo: Implications for development of a therapy for poxvirus infection [2].
• The solution structure of the N-terminal domain of E3L shows a tyrosine conformation that may explain its reduced affinity to Z-DNA in vitro [7].

Biological context of E3L

• Overall, this work suggests that the important role of E3L in VV pathogenesis involves modulating expression of host cellular genes at the transcriptional level and inhibiting apoptosis of host cells through Z-DNA binding [6].
• Mutations decreasing Z-DNA binding in the chimera correlate with decreases in viral pathogenicity, as do analogous mutations in wild-type E3L [3].
• Comparison of the deduced amino acid sequence of the E3L gene products with the protein sequence data base revealed a region closely related to the human interferon-induced, double-stranded RNA-activated protein kinase [1].
• Expression of E3L in NIH3T3 cells results in inhibition of eIF-2alpha phosphorylation and Ikappa(B)alpha degradation in response to dsRNA [8].
• To investigate the relevance of E3L in the MVA life cycle, we generated the deletion mutant MVA-DeltaE3L [9].

Anatomical context of E3L

• In addition, COS cells expressing E3L gene products inhibited activation of the double-stranded RNA-activated protein kinase in extracts from interferon-treated cells [1].
• The WR strain E3L gene was cloned and expressed either in COS-1 cells or in rabbit reticulocyte lysates in vitro [1].
• To analyse E3L effects over cellular metabolism in a virus-free system, we have generated stable mouse 3T3 cell lines expressing E3L [8].
• Vaccinia virus from which the E3L gene has been deleted (VVDeltaE3L) is highly sensitive to interferon and exhibits a restricted host range, replicating very inefficiently in many cell types, including human fibroblast and U373MG cells [10].
• Infection with wild-type vaccinia virus failed to induce germ line epsilon expression; however, a deletion mutant of vaccinia virus (VP1080) lacking the PKR-inhibitory polypeptide E3L induced the expression of germ line epsilon [11].

Associations of E3L with chemical compounds

• We also demonstrated that the E3L protein can bind to nuclei of aldehyde fixed and detergent permeabilized uninfected cells [12].
• The RNA start site of an early promoter was located 26 nucleotides upstream of the first methionine codon of E3L [12].
• With natural neurotransmitter pre-mRNA substrates, E3L weakly inhibited the site-selective editing activity by ADAR1 at the R/G site of the glutamate receptor B subunit (GluR-B) pre-mRNA and the A site of serotonin 2C receptor (5-HT2CR) pre-mRNA; editing of the intronic hotspot (+)60 site of GluR-B was not affected by E3L [13].

Regulatory relationships of E3L

• Analysis in vitro demonstrated that the E3L gene product inhibited PKR approximately 50- to 100-fold more efficiently than the K3L gene product [14].

Other interactions of E3L

• In addition, neither K3L nor E3L expression detectably altered cellular protein synthesis [14].
• For each protein at least 13 measured masses matched, within less than 0.1 Da, calculated tryptic peptides of the vaccinia virus proteins H5R (34 kDa), E3L (24 kDa) and E5R (45 kDa) [15].

Analytical, diagnostic and therapeutic context of E3L

• The recombinant VV (VV/ORF-E3L) expressing the OV E3L homologue in place of VV E3L was indistinguishable from wt VV in its cell-culture phenotype [16].

References