Regulation of hypoxia-inducible factor 1α is mediated by an O ₂ -dependent degradation domain via the ubiquitin-proteasome pathway

TLDR

Hypoxia induces genes such as erythropoietin and VEGF, which are transcriptionally up‑regulated by HIF‑1, a bHLH‑PAS regulator whose activity is largely governed by the oxygen‑dependent stabilization of its α subunit, HIF‑1α, otherwise rapidly degraded in normoxia. The study identifies an oxygen‑dependent degradation (ODD) domain within HIF‑1α that mediates its ubiquitin‑proteasome–dependent degradation. The ODD comprises roughly 200 amino acids located in the central region of HIF‑1α. Removal of the entire ODD produces a stable HIF‑1α capable of heterodimerization, DNA binding, and transactivation without hypoxia, while the ODD alone confers oxygen‑dependent instability when fused to Gal4, underscoring its central role in regulating HIF‑1 activity and oxygen‑mediated gene expression.

Abstract

Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of α and β subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1α, which is otherwise rapidly degraded in oxygenated cells. We report the identification of an oxygen-dependent degradation (ODD) domain within HIF-1α that controls its degradation by the ubiquitin-proteasome pathway. The ODD domain consists of ≈200 amino acid residues, located in the central region of HIF-1α. Because portions of the domain independently confer degradation of HIF-1α, deletion of this entire region is required to give rise to a stable HIF-1α, capable of heterodimerization, DNA-binding, and transactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a stable protein, Gal4. Hence, the ODD domain plays a pivotal role for regulating HIF-1 activity and thereby may provide a means of controlling gene expression by changes in oxygen tension.