Prolyl hydroxylase EGLN3

Function

Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4, GPX4 and HIF1A. Target proteins are preferentially recognized via a LXXLAP motif. Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. Acts as an inhibitor of ferroptosis by mediating hydroxylation of GPX4, thereby preventing GPX4 degradation via chaperone-mediated autophagy. GPX4 hydroxylation is promoted by PSAT1, which provides 2-oxoglutarate substrate to EGLN3. ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (Probable).

Classification

Family (Pfam)

PF13640 2OG-FeII_Oxy_3

InterPro

HIF_prolyl_hydroxylases, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, Pro_4_hyd_alph_FE2OG_OXY

Functional cluster

Zinc-Finger Nucleic-Acid-Binding & Methyltransferases

Gene Ontology · 16

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0016706 2-oxoglutarate-dependent dioxygenase activity
• GO:0008198 ferrous iron binding
• GO:0160082 hypoxia-inducible factor-proline dioxygenase activity
• GO:0031418 L-ascorbic acid binding
• GO:0031545 peptidyl-proline 4-dioxygenase activity
• GO:0006915 apoptotic process
• GO:0071456 cellular response to hypoxia
• GO:0006974 DNA damage response
• GO:0110076 negative regulation of ferroptosis
• GO:0018126 protein hydroxylation
• GO:0050821 protein stabilization
• GO:0043523 regulation of neuron apoptotic process

Drugs targeting this protein · 4

• ROXADUSTAT inhibitor
• DAPRODUSTAT inhibitor
• MOLIDUSTAT inhibitor
• VADADUSTAT inhibitor

Related proteins · sequence + function similarity

• Prolyl hydroxylase EGLN3 0.99
• Prolyl hydroxylase EGLN3 0.99
• Egl nine homolog 1 0.68
• Egl nine homolog 1 0.61
• Prolyl 3,4-dihydroxylase OGFOD1 0.60
• Prolyl 3-hydroxylase sudestada1 0.60
• Prolyl hydroxylase EGLN2 0.60
• Egl nine homolog 1 0.59
• 2-oxoglutarate and iron-dependent oxygenase domain-containing protein CP2 0.59
• 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 2 0.59
• 2-oxoglutarate and iron-dependent oxygenase domain-containing protein ICU11 0.59
• Prolyl hydroxylase EGLN2 0.58

Co-cited proteins · studied together in the literature

• Egl nine homolog 1 10 shared papers
• Prolyl hydroxylase EGLN2 9 shared papers
• Prolyl hydroxylase EGLN3 3 shared papers
• Paired box protein Pax-2 1 shared papers
• Pyruvate kinase PKM 2 shared papers
• Telomere length regulation protein TEL2 homolog 1 shared papers
• Prolyl hydroxylase EGLN3 2 shared papers
• Phosphoserine aminotransferase 1 shared papers
• Transmembrane prolyl 4-hydroxylase 1 shared papers
• Cyclic AMP-dependent transcription factor ATF-4 1 shared papers
• Phospholipid hydroperoxide glutathione peroxidase GPX4 1 shared papers
• Egl nine homolog 1 1 shared papers

Literature · 26 cited papers

• PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation. Nat. Chem. Biol. · 2025
• PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response. J. Clin. Invest. · 2012
• The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat. Cell Biol. · 2012
• Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell · 2011
• Prolyl hydroxylase domain protein 3 targets Pax2 for destruction. Biochem. Biophys. Res. Commun. · 2011
• The oxygen sensor PHD3 limits glycolysis under hypoxia via direct binding to pyruvate kinase. Cell Res. · 2011
• Effects of polynitrogen compounds on the activity of recombinant human HIF-1alpha prolyl hydroxylase 3 in E. coli. J. Inorg. Biochem. · 2011
• Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites. Biochem. J. · 2011
• Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J. Clin. Invest. · 2011
• PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br. J. Cancer · 2010
• Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells. Biochem. Biophys. Res. Commun. · 2010
• Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci. Signal. · 2009
• … and 14 more in the literature graph