HCMV IE2-mediated inhibition of HAT activity downregulates p53 function.
Targeting of cellular histone acetyltransferases (HATs) by viral proteins is important in the development of virus-associated diseases. The immediate-early 2 protein (IE2) of human cytomegalovirus (HCMV) binds to the tumor suppressor, p53, and inactivates its functions by unknown mechanisms. Here, we show that IE2 binds to the HAT domain of the p53 coactivators, p300 and CREB-binding protein (CBP), and blocks their acetyltransferase activity on both histones and p53. The minimal HAT inactivation region on IE2 involves the N-terminal 98 amino acids. The in vivo DNA binding of p53 and local histone acetylation on p53-dependent promoters are all reduced by IE2, but not by mutant IE2 proteins that lack the HAT inhibition region. Furthermore, the p53 acetylation site mutant, K320/373/382R, retains both DNA binding and promoter transactivation activity in vivo and these effects are repressed by IE2 as well. Together with the finding that only wild-type IE2 exerts an antiapoptotic effect, our results suggest that HCMV IE2 downregulates p53-dependent gene activation by inhibiting p300/CBP-mediated local histone acetylation and that IE2 may have oncogenic activity.
Hsu
Chih-Hung
CH
Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
Chang
Margaret D T
MD
Tai
Kang-Yu
KY
Yang
Yu-Ting
YT
Wang
Pei-Shan
PS
Chen
Chi-Ju
CJ
Wang
Yan-Hsiung
YH
Lee
Sheng-Chung
SC
Wu
Cheng-Wen
CW
Juan
Li-Jung
LJ
D000123:Acetyltransferases; D000595:Amino Acid Sequence; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017304:Annexin A5; D017362:Cyclic AMP Response Element-Binding Protein; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000123:Acetyltransferases; D051548:Histone Acetyltransferases