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-1α 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-1α to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1α with pVHL and HIF-1α ubiquitination, suggesting that the acetylation of HIF-1α by ARD1 is critical to proteasomal degradation. Therefore, we have concluded that the role of ARD1 in the acetylation of HIF-1α provides a key regulatory mechanism underlying HIF-1α stability.
Bibliographical noteFunding Information:
We thank Dr. Fujii-Kuriyama for his gifts of the pBOS-hHIF-1α, pBOS-hARNT, and pSV40pro-EpoHRE-Luc vectors; Dr. Jong-Wan Park for the anti-HIF-1α antibody; Dr. L. Eric Huang for the mutated EpoHRE-Luc vector; and Dr. Byung Pal Yu for the critical reading of the manuscript. Financial support was provided by the National Research Laboratory Fund (2001-N-NL-01-C-015), the Ministry of Science and Technology, Korea (to K.-W.K.).