Spermidine/spermine N(1)-acetyltransferase-1 binds to hypoxia-inducible factor-1alpha (HIF-1alpha) and RACK1 and promotes ubiquitination and degradation of HIF-1alpha.
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of oxygen homeostasis that controls the expression of genes encoding proteins that play key roles in angiogenesis, erythropoiesis, and glucose/energy metabolism. The stability of the HIF-1alpha subunit is regulated by ubiquitination and proteasomal degradation. In aerobic cells, O(2)-dependent prolyl hydroxylation of HIF-1alpha is required for binding of the von Hippel-Lindau tumor suppressor protein VHL, which then recruits the Elongin C ubiquitin-ligase complex. SSAT2 (spermidine/spermine N-acetyltransferase-2) binds to HIF-1alpha and promotes its ubiquitination/degradation by stabilizing the interaction of VHL and Elongin C. Treatment of cells with heat shock protein HSP90 inhibitors induces the degradation of HIF-1alpha even under hypoxic conditions. HSP90 competes with RACK1 for binding to HIF-1alpha, and HSP90 inhibition leads to increased binding of RACK1, which recruits the Elongin C ubiquitin-ligase complex to HIF-1alpha in an O(2)-independent manner. In this work, we demonstrate that SSAT1, which shares 46% amino acid identity with SSAT2, also binds to HIF-1alpha and promotes its ubiquitination/degradation. However, in contrast to SSAT2, SSAT1 acts by stabilizing the interaction of HIF-1alpha with RACK1. Thus, the paralogs SSAT1 and SSAT2 play complementary roles in promoting O(2)-independent and O(2)-dependent degradation of HIF-1alpha.
Baek
Jin H
JH
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Liu
Ye V
YV
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
McDonald
Karin R
KR
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Wesley
Jacob B
JB
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Zhang
Huafeng
H
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Semenza
Gregg L
GL
Vascular Program, Institute for Cell Engineering, the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Electronic address: gsemenza@jhmi.edu.
D000123:Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D000075065:Elongin; D019204:GTP-Binding Proteins / Q000737:chemistry*; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000075065:Elongin; D019204:GTP-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D010100:Oxygen; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D025801:Ubiquitin; D000099228:Diamine N-Acetyltransferase; C000616395:ELOC protein, human; C419368:RACK1 protein, human