Identification of oleoylethanolamide as an endogenous ligand for HIF-3α

Journal article

Hypoxia-inducible factors (HIFs) are α/β heterodimeric transcription factors modulating cellular responses to the low oxygen condition. Among three HIF-α isoforms, HIF-3α is the least studied to date. Here we show that oleoylethanolamide (OEA), a physiological lipid known to regulate food intake and metabolism, binds selectively to HIF-3α. Through crystallographic analysis of HIF-3 α/β heterodimer in both apo and OEA-bound forms, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics (MD) simulations, and biochemical and cell-based assays, we unveil the molecular mechanism of OEA entry and binding to the PAS-B pocket of HIF-3α, and show that it leads to enhanced heterodimer stability and functional modulation of HIF-3. The identification of HIF-3α as a selective lipid sensor is consistent with recent human genetic findings linking HIF-3α with obesity, and demonstrates that endogenous metabolites can directly interact with HIF-α proteins to modulate their activities, potentially as a regulatory mechanism supplementary to the well-known oxygen-dependent HIF-α hydroxylation.

Authors: Diao, X; Ye, F; Zhang, M; Ren, X; Tian, X

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 2529-2529
• Article number: 2529
• Publication date: 2022-05-09
• DOI: 10.1038/s41467-022-30338-z
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Hypoxia-inducible factors; Biology; Gene isoform; Hydroxylation; Cell biology; Biochemistry; Transcription factor; Chemistry; Receptor; Gene; Endogeny; Enzyme