Jeong Joo Won, Bae Moon Kyoung, Ahn Mee Young, Kim Se Hee, Sohn Tae Kwon, Bae Myung Ho, Yoo Mi Ae, Song Eun Joo, Lee Kong Joo, Kim Kyu Won
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 151-742, Seoul, South Korea.
Cell. 2002 Nov 27;111(5):709-20. doi: 10.1016/s0092-8674(02)01085-1.
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.
缺氧诱导因子1（HIF-1）在细胞适应氧供应变化中起核心作用。最近，脯氨酰羟化被确定为一个关键的调节事件，它通过pVHL泛素化复合体将HIF-1α亚基靶向蛋白酶体降解。在本报告中，我们揭示了ARD1在哺乳动物细胞中作为一种蛋白质乙酰转移酶的重要功能，它通过直接结合HIF-1α来调节其稳定性。我们进一步提供证据表明，ARD1介导的乙酰化增强了HIF-1α与pVHL的相互作用以及HIF-1α的泛素化，这表明ARD1对HIF-1α的乙酰化对于蛋白酶体降解至关重要。因此，我们得出结论，ARD1在HIF-1α乙酰化中的作用为HIF-1α稳定性提供了关键的调节机制。
