Proteasome-dependent degradation of Daxx by the viral E1B-55K protein in human adenovirus-infected cells.
The death-associated protein Daxx found in PML (promyelocytic leukemia protein) nuclear bodies (PML-NBs) is involved in transcriptional regulation and cellular intrinsic antiviral resistence against incoming viruses. We found that knockdown of Daxx in a nontransformed human hepatocyte cell line using RNA interference (RNAi) techniques results in significantly increased adenoviral (Ad) replication, including enhanced viral mRNA synthesis and viral protein expression. This Daxx restriction imposed upon adenovirus growth is counteracted by early protein E1B-55K (early region 1B 55-kDa protein), a multifunctional regulator of cell-cycle-independent Ad5 replication. The viral protein binds to Daxx and induces its degradation through a proteasome-dependent pathway. We show that this process is independent of Ad E4orf6 (early region 4 open reading frame 6), known to promote the proteasomal degradation of cellular p53, Mre11, DNA ligase IV, and integrin alpha3 in combination with E1B-55K. These results illustrate the importance of the PML-NB-associated factor Daxx in virus growth restriction and suggest that E1B-55K antagonizes innate antiviral activities of Daxx and PML-NBs to stimulate viral replication at a posttranslational level.
Schreiner
Sabrina
S
Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistr. 52, 20251 Hamburg, Germany.
Wimmer
Peter
P
Sirma
Hüseyin
H
Everett
Roger D
RD
Blanchette
Paola
P
Groitl
Peter
P
Dobner
Thomas
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005814:Genes, Viral; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology / Q000821:virology*; D006801:Humans; D000076228:MRE11 Homologue Protein; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D017501:Adenovirus E1B Proteins; C496871:CUL5 protein, human; D056970:Co-Repressor Proteins; D044842:Cullin Proteins; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D012367:RNA, Viral; D014764:Viral Proteins; D000076228:MRE11 Homologue Protein; D046988:Proteasome Endopeptidase Complex