title: The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5.
abstract: The V protein of simian virus 5 (SV5) blocks interferon signaling by targeting STAT1 for proteasome-mediated degradation. Here we present three main pieces of evidence which demonstrate that the p127 subunit (DDB1) of the UV damage-specific DNA binding protein (DDB) plays a central role in this degradation process. First, the V protein of an SV5 mutant which fails to target STAT1 for degradation does not bind DDB1. Second, mutations in the N and C termini of V which abolish the binding of V to DDB1 also prevent V from blocking interferon (IFN) signaling. Third, treatment of HeLa/SV5-V cells, which constitutively express the V protein of SV5 and thus lack STAT1, with short interfering RNAs specific for DDB1 resulted in a reduction in DDB1 levels with a concomitant increase in STAT1 levels and a restoration of IFN signaling. Furthermore, STAT1 is degraded in GM02415 (2RO) cells, which have a mutation in DDB2 (the p48 subunit of DDB) which abolishes its ability to interact with DDB1, thereby demonstrating that the role of DDB1 in STAT1 degradation is independent of its association with DDB2. Evidence is also presented which demonstrates that STAT2 is required for the degradation of STAT1 by SV5. These results suggest that DDB1, STAT1, STAT2, and V may form part of a large multiprotein complex which leads to the targeted degradation of STAT1 by the proteasome.
authors.affiliation: School of Biology, University of St. Andrews, Fife KY16 9TS, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Andrejeva
authors.forename: E
authors.initials: E
authors.lastname: Poole
authors.forename: D F
authors.initials: DF
authors.lastname: Young
authors.forename: S
authors.initials: S
authors.lastname: Goodbourn
authors.forename: R E
authors.initials: RE
authors.lastname: Randall
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000378:metabolism; D010223:Parainfluenza Virus 2, Human / Q000472:pathogenicity / Q000502:physiology; D019213:Rubulavirus / Q000472:pathogenicity* / Q000502:physiology; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014764:Viral Proteins; D015678:Viral Structural Proteins / Q000378:metabolism*; D014779:Virus Replication; D014983:Xeroderma Pigmentosum / Q000378:metabolism
chemical_list: C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D015534:Trans-Activators; C097019:V protein, Simian parainfluenza virus 5; C068854:V protein, human parainfluenza virus type 1; D014764:Viral Proteins; D015678:Viral Structural Proteins; D007372:Interferons