Ectromelia virus encodes a family of Ankyrin/F-box proteins that regulate NFκB

•Ectromelia virus encodes four Ank/F-box proteins, EVM002, EVM005, EVM154 and EVM165.•The Ank/F-box proteins inhibit NFκB nuclear translocation, dependent on the F-box.•The Ank/F-box proteins prevent IκBα degradation, suggesting they target the SCF.•Deletion of a single Ank/F-box gene from ECTV does not prevent viral NFκB inhibition.•This study identifies a new mechanism by which ectromelia virus inhibits NFκB.

A notable feature of poxviruses is their ability to inhibit the antiviral response, including the nuclear factor kappa B (NFκB) pathway. NFκB is a transcription factor that is sequestered in the cytoplasm until cell stimulation, and relies on the SCF (Skp1, culllin-1, F-box) ubiquitin ligase to target its inhibitor, IκBα, for degradation. IκBα is recruited to the SCF by the F-box domain-containing protein βTrCP. Here, we show that ectromelia virus, the causative agent of mousepox, encodes four F-box-containing proteins, EVM002, EVM005, EVM154, and EVM165, all of which contain Ankyrin (Ank) domains. The Ank/F-box proteins inhibit NFκB nuclear translocation, and this inhibition is dependent on the F-box domain. We also demonstrate that EVM002, EVM005, EVM154, and EVM165 prevent IκBα degradation, suggesting that they target the SCF. This study identifies a new mechanism by which ectromelia virus inhibits NFκB.