The African swine fever virus MGF505-1R protein recruits the cullin-RING-ligase machinery to promote p300 degradation.

African swine fever virus (ASFV) is a large, complex DNA virus that causes a haemorrhagic disease with lethality rates approaching 100%. Mechanisms of virulence are still poorly understood, but loss of members of the multigene families (MGF) is commonly observed in naturally occurring attenuated virus strains, indicating that these proteins play an important role in disease pathogenesis. Here, a suppressor of cytokine signalling (SOCS)-box like motif was identified in proteins of the MGF505 cluster. SOCS-box motifs typically recruit the Cullin-RING-ligase (CRL) machinery, a superfamily of E3 ubiquitin ligases that target proteins for proteasomal degradation. Data presented show that MGF505-1R inhibits the host innate immune responses controlled by the activation of the transcription factors IRF3 and NFκB. MGF505‑1R expression was shown to correlate with a reduction in the protein levels of the transcriptional co‑activator p300. Targeted mutations of the SOCS box motif were shown to reverse the observed IRF3 and NFκB inhibition. The data support a role for MGF505-1R in hijacking the host ubiquitin machinery to evade the host immune responses.