Spermidine/spermine N1-acetyltransferase-1 binds to hypoxia-inducible factor-1α (HIF-1α) and RACK1 and promotes ubiquitination and degradation of HIF-1α

Jin H. Baek, Ye V. Liu, Karin R. McDonald, Jacob B. Wesley, Huafeng Zhang, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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-1α subunit is regulated by ubiquitination and proteasomal degradation. In aerobic cells, O2-dependent prolyl hydroxylation of HIF-1α 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-1α 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-1α even under hypoxic conditions. HSP90 competes with RACK1 for binding to HIF-1α, and HSP90 inhibition leads to increased binding of RACK1, which recruits the Elongin C ubiquitin-ligase complex to HIF-1α in an O2-independent manner. In this work, we demonstrate that SSAT1, which shares 46% amino acid identity with SSAT2, also binds to HIF-1α and promotes its ubiquitination/ degradation. However, in contrast to SSAT2, SSAT1 acts by stabilizing the interaction of HIF-1α with RACK1. Thus, the paralogs SSAT1 and SSAT2 play complementary roles in promoting O2-independent and O 2-dependent degradation of HIF-1α.

Original languageEnglish (US)
Pages (from-to)33358-33366
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number46
DOIs
StatePublished - Nov 16 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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