Regulation of the 26S proteasome by adenovirus E1A.
We have identified the N-terminus of adenovirus early region 1A (AdE1A) as a region that can regulate the 26S proteasome. Specifically, in vitro and in vivo co-precipitation studies have revealed that the 19S regulatory components of the proteasome, Sug1 (S8) and S4, bind through amino acids (aa) 4-25 of Ad5 E1A. In vivo expression of wild-type (wt) AdE1A, in contrast to the N-terminal AdE1A mutant that does not bind the proteasome, reduces ATPase activity associated with anti-S4 immunoprecipitates relative to mock-infected cells. This reduction in ATPase activity correlates positively with the ability of wt AdE1A, but not the N-terminal deletion mutant, to significantly reduce the ability of HPV16 E6 to target p53 for ubiquitin-mediated proteasomal degradation. AdE1A/proteasomal complexes are present in both the cytoplasm and the nucleus, suggesting that AdE1A interferes with both nuclear and cytoplasmic proteasomal degradation. We have also demonstrated that wt AdE1A and the N-terminal AdE1A deletion mutant are substrates for proteasomal-mediated degradation. AdE1A degradation is not, however, mediated through ubiquitylation, but is regulated through phosphorylation of residues within a C-terminal PEST region (aa 224-238).
Turnell
A S
AS
CRC Institute for Cancer Studies, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. A.S.Turnell@bham.ac.uk
Grand
R J
RJ
Gorbea
C
C
Zhang
X
X
Wang
W
W
Mymryk
J S
JS
Gallimore
P H
PH
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000378:metabolism; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins; D013379:Substrate Specificity; D014157:Transcription Factors; D014452:Ubiquitins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; C068651:E6 protein, Human papillomavirus type 16; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009856:Oncogene Proteins, Viral; C092282:PSMC5 protein, human; D012097:Repressor Proteins; C106843:SUG1 protein, mammalian; D014157:Transcription Factors; D014452:Ubiquitins; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases