Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation.
Hypoxia-inducible factor 1 (HIF-1) plays a central role in cellular adaptation to changes in oxygen availability. Recently, prolyl hydroxylation was identified as a key regulatory event that targets the HIF-1alpha subunit for proteasomal degradation via the pVHL ubiquitination complex. In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1alpha to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1alpha with pVHL and HIF-1alpha ubiquitination, suggesting that the acetylation of HIF-1alpha by ARD1 is critical to proteasomal degradation. Therefore, we have concluded that the role of ARD1 in the acetylation of HIF-1alpha provides a key regulatory mechanism underlying HIF-1alpha stability.
Jeong
Joo Won
JW
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 151-742, Seoul, South Korea.
Bae
Moon Kyoung
MK
Ahn
Mee Young
MY
Kim
Se Hee
SH
Sohn
Tae Kwon
TK
Bae
Myung Ho
MH
Yoo
Mi Ae
MA
Song
Eun Joo
EJ
Lee
Kong Joo
KJ
Kim
Kyu Won
KW
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; C097081:PPP1R8 protein, human; D010100:Oxygen