Spermidine/Spermine-N1-Acetyltransferase 2 Is an Essential Component of the Ubiquitin Ligase Complex That Regulates Hypoxia-inducible Factor 1α

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1α subunit is subjected to O2-dependent prolyl hydroxylation leading to ubiquitination by the von Hippel-Lindau protein (VHL)-Elongin C ubiquitin-ligase complex and degradation by the 26 S proteasome. In this study, we demonstrate that spermidine/spermine-N1-acetyltransferase (SSAT) 2 plays an essential role in this process. SSAT2 binds to HIF-1α, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1α by stabilizing the interaction of VHL and Elongin C. Multivalent interactions by SSAT2 provide a mechanism to ensure efficient complex formation, which is necessary for the extremely rapid ubiquitination and degradation of HIF-1α that is observed in oxygenated cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1α subunit is subjected to O2-dependent prolyl hydroxylation leading to ubiquitination by the von Hippel-Lindau protein (VHL)-Elongin C ubiquitin-ligase complex and degradation by the 26 S proteasome. In this study, we demonstrate that spermidine/spermine-N1-acetyltransferase (SSAT) 2 plays an essential role in this process. SSAT2 binds to HIF-1α, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1α by stabilizing the interaction of VHL and Elongin C. Multivalent interactions by SSAT2 provide a mechanism to ensure efficient complex formation, which is necessary for the extremely rapid ubiquitination and degradation of HIF-1α that is observed in oxygenated cells. Oxygen homeostasis represents a critical organizing principle of metazoan evolution and biology (1Fisher S.A. Burggren W.W. Antioxid Redox Signal. 2007; (, in press)PubMed Google Scholar, 2Semenza G.L. Biochem. J. 2007; 405: 1-9Crossref PubMed Google Hypoxia-inducible factor 1 (HIF-1) prolyl VHL, von Hippel-Lindau in and prolyl VHL, von Hippel-Lindau in and functions as a master regulator of oxygen homeostasis in metazoan as as an of for to an complex and to and to of (1Fisher S.A. Burggren W.W. Antioxid Redox Signal. 2007; (, in press)PubMed Google Scholar, G.L. PubMed Google Scholar, J. J. PubMed Google Scholar, J. PubMed Google Scholar, G.L. PubMed Google Scholar, C. PubMed Google of and is for of and that in is necessary for the of and of the G.L. Biochem. J. 2007; 405: 1-9Crossref PubMed Google Scholar, G.L. 2007; PubMed Google this essential the transcription of of G.L. PubMed Google Scholar, J. J. PubMed Google that for of the and G.L. PubMed Google Scholar, J. J. PubMed Google Scholar, PubMed Google and essential in to and in PubMed Google Scholar, G.L. PubMed Google Scholar, G.L. PubMed Google of the complex of that the G.L. G.L. PubMed Google G.L. G.L. J. 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