Sumoylation increases HIF-1alpha stability and its transcriptional activity.
HIF-1 is closely involved in various biological processes, including angiogenesis, energy metabolism, and cell survival. HIF-1 consists of an oxygen-sensitive HIF-1alpha and oxygen-insensitive HIF-1beta. Oxygen-sensitive HIF-1alpha is subjected to post-translational modifications such as hydroxylation, ubiquitination, and acetylation, which are related to the regulation of its stability. In this present study, we found that the ectopic expression of SUMO-1 increased HIF-1alpha stability by the co-transfection study with HIF-1alpha and SUMO-1. Furthermore, the ectopic expression of SUMO-1 enhanced the transcriptional activity of HIF-1alpha. In the subsequent immunoprecipitation assay, SUMO-1 was co-immunoprecipitated with HIF-1alpha, implying that HIF-1alpha is covalently modified by SUMO-1. Thereafter, using a series of lysine mutants in the ODD domain, we found that HIF-1alpha was sumoylated at Lys(391) and Lys(477), suggesting that sumoylation at these two lysine residues enhances HIF-1alpha stability by possibly modulating other post-translational modifications. Altogether, we demonstrate that HIF-1alpha is upregulated through SUMO-1 modification at Lys(391)/Lys(477) residues, which may stabilize HIF-1alpha and enhance its transcriptional activity.
Division of Pharmaceutical Bioscience, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Seong-Hui
SH
Bae
Joo-Won
JW
Jeong
Jeong Ae
JA
Park
Se-Hee
SH
Kim
Moon-Kyoung
MK
Bae
Soo-Joon
SJ
Choi
Kyu-Won
KW
Kim
D000595:Amino Acid Sequence; D000818:Animals; D004795:Enzyme Stability; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025842:SUMO-1 Protein; D014157:Transcription Factors; D008239:Lysine