Leaky scanning translation generates a second A49 protein that contributes to vaccinia virus virulence.

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Neidel, Sarah 
Torres, Alice A 
Ren, Hongwei 
Smith, Geoffrey L 

Vaccinia virus (VACV) strain Western Reserve gene A49L encodes a small intracellular protein with a Bcl-2 fold that is expressed early during infection and has multiple functions. A49 co-precipitates with the E3 ubiquitin ligase β-TrCP and thereby prevents ubiquitylation and proteasomal degradation of IκBα, and consequently blocks activation of NF-κB. In a similar way, A49 stabilizes β-catenin, leading to activation of the wnt signalling pathway. However, a VACV strain expressing a mutant A49 that neither co-precipitates with β-TrCP nor inhibits NF-κB activation, is more virulent than a virus lacking A49, indicating that A49 has another function that also contributes to virulence. Here we demonstrate that gene A49L encodes a second, smaller polypeptide that is expressed via leaky scanning translation from methionine 20 and is unable to block NF-κB activation. Viruses engineered to express either only the large protein or only the small A49 protein both have lower virulence than wild-type virus and greater virulence than an A49L deletion mutant. This demonstrates that the small protein contributes to virulence by an unknown mechanism that is independent of NF-κB inhibition. Despite having a large genome with about 200 genes, this study illustrates how VACV makes efficient use of its coding potential and from gene A49L expresses a protein with multiple functions and multiple proteins with different functions.

Bcl2-fold, NF-κB inhibitor, gene A49R, leaky scanning, multiple functions, vaccinia virus, virulence, Animals, Female, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, NF-KappaB Inhibitor alpha, NF-kappa B, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination, Vaccinia, Vaccinia virus, Viral Proteins, Virulence, beta-Transducin Repeat-Containing Proteins
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J Gen Virol
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Microbiology Society
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Wellcome Trust (090315/Z/09/Z)
Wellcome Trust (090315/B/09/A)