Identification of DNA-damage DNA-binding protein 1 as a conditional essential factor for cytomegalovirus replication in interferon-γ-stimulated cells

The mouse cytomegaloviral (mcmv) protein pm27 represents an indispensable factor for viral fitness in vivo selectively,antagonizing signal transducer and activator of transcription 2 (stat2)-mediated interferon signal transduction. we wished to explore by which molecular mechanism pm27 accomplishes this effect. we demonstrate that pm27 is essential and sufficient to curtail the protein half-life of stat2 molecules. pharmacologic inhibition of the proteasome restored stat2 amounts,leading to poly-ubiquitin-conjugated stat2 forms. pm27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein,dna-damage dna-binding protein (ddb) 1. truncation mutants of pm27 showed a strict correlation between ddb1 interaction and their ability to degrade stat2. sirna-mediated knock-down of ddb1 restored stat2 in the presence of pm27 and strongly impaired viral replication in interferon conditioned cells,thus phenocopying the growth attenuation of m27-deficient virus. in a constructive process,pm27 recruits ddb1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the stat2-dependent antiviral state of cells to permit viral replication. © 2011 trilling et al.