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.
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Int Immunopharmacol
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Department of Spine Surgery, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong 250000, China; Department of Spine Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250000, China. Electronic address:
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Department of Pathology, Northwestern University, Chicago, IL, USA.
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Department of Otolaryngology Head and Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu, China.
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Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China.
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Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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