Vaccinia virus E3L interferon resistance protein inhibits the interferon-induced adenosine deaminase A-to-I editing activity.
The RNA-specific adenosine deaminase (ADAR1) is an interferon-inducible editing enzyme that converts adenosine to inosine. ADAR1 contains three distinct domains: a N-terminal Z-DNA binding domain that includes two Z-DNA binding motifs; a central double-stranded RNA binding domain that includes three dsRNA binding motifs (dsRBM); and a C-terminal catalytic domain responsible for A-to-I enzymatic activity. The E3L protein of vaccinia virus mediates interferon resistance. E3L, similar to ADAR1, also contains Z-DNA binding and dsRNA binding motifs. To assess the possible role of E3L in modulating RNA editing by ADAR1, we examined the effect of E3L on ADAR1 deaminase activity. Wild-type E3L protein was a potent inhibitor of ADAR1 deaminase enzymatic activity. Analysis of mutant E3L proteins indicated that the carboxy-proximal dsRBM of E3L was essential for antagonism of ADAR1. Surprisingly, disruption of the Z-DNA binding domain of E3L by double substitutions of two highly conserved residues also abolished its antagonistic activity, whereas deletion of the entire Z domain had little effect on the inhibition. 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. These results demonstrate that the A-to-I RNA editing activity of the IFN-inducible adenosine deaminase is impaired by the product of the vaccinia virus E3L interferon resistance gene.
Liu
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Y
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.
Wolff
K C
KC
Jacobs
B L
BL
Samuel
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CE
D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D007288:Inosine / Q000378:metabolism; D007372:Interferons / Q000494:pharmacology; D009154:Mutation; D017393:RNA Editing / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014616:Vaccinia virus / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D058892:Adenosine Deaminase Inhibitors; C081374:E3L protein, Vaccinia virus; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D007288:Inosine; D007372:Interferons; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine