Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1alpha.
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that functions as a master regulator of oxygen homeostasis. The HIF-1alpha subunit is subjected to O(2)-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-N(1)-acetyltransferase (SSAT) 2 plays an essential role in this process. SSAT2 binds to HIF-1alpha, VHL, and Elongin C and promotes ubiquitination of hydroxylated HIF-1alpha 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-1alpha that is observed in oxygenated cells.
Baek
Jin Hyen
JH
Vascular Biology Program, Institute for Cell Engineering, Department of Pediatrics, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Liu
Ye V
YV
McDonald
Karin R
KR
Wesley
Jacob B
JB
Hubbi
Maimon E
ME
Byun
Hweejo
H
Semenza
Gregg L
GL
D000123:Acetyltransferases / Q000737:chemistry* / Q000502:physiology*; D002460:Cell Line; D000075065:Elongin; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000502:physiology*; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011485:Protein Binding; D014157:Transcription Factors / Q000737:chemistry; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000075065:Elongin; D005982:Glutathione Transferase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D046988:Proteasome Endopeptidase Complex; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099228:Diamine N-Acetyltransferase; C000616395:ELOC protein, human; C497442:HIF1A protein, human; C061553:ATP dependent 26S protease; C497446:VHL protein, human