Abstract

Poxviruses like vaccinia virus (VACV), the smallpox vaccine, have linear double-stranded DNA genomes encoding ~200 genes. Almost half of these genes are implicated in subverting the innate and adaptive immune response of hosts and many closely resemble host genes, suggesting that the viruses hijacked these genes and exploit them to their benefit.

The Bcl-2 family comprises a number of small cellular proteins that modulate apoptosis. We solved the crystal structures of VACV proteins A52 and B14 and showed that they adopt the same fold as cellular Bcl-2 proteins despite an absence of sequence homology. Rather than modulating apoptosis, A52 and B14 have evolved to inhibit activation of the pro-inflammatory transcription factor NF-kB. Additionally, we found that the Bcl2-like VACV protein N1 inhibits both apoptosis and NF-kB activation via two distinct molecular surfaces. Our recent work shows that the family of poxvirus Bcl-2 proteins is more extensive than previously supposed, highlighting the utility of this small protein fold in modulating pro-viral protein:protein interactions.