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MGP006322

UniProt Annotations

Entry Information
Gene Nameegl-9 family hypoxia-inducible factor 3
Protein EntryEGLN3_HUMAN
UniProt IDQ9H6Z9
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityHypoxia-inducible factor-L-proline + 2- oxoglutarate + O(2) = hypoxia-inducible factor-trans-4-hydroxy-L- proline + succinate + CO(2). {ECO:0000269|PubMed:11598268}.
CofactorName=Fe(2+); Xref=ChEBI:CHEBI:29033; Note=Binds 1 Fe(2+) ion per subunit.;
CofactorName=L-ascorbate; Xref=ChEBI:CHEBI:38290;
DomainThe Beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity.
Enzyme RegulationActivated in cardiovascular cells and Hela cells following exposure to hypoxia. Inhibited by polynitrogen compounds probably by chelation to Fe(2+) ions. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21421125}.
FunctionCellular 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. EGLN3 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. Target proteins are preferencially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16098468, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300}.
InductionInduced by hypoxia in a number of cells including neutrophils and certain cancer cell lines. Up-regulated 10-fold in pancreatic cancers. {ECO:0000269|PubMed:12615973, ECO:0000269|PubMed:15247232, ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538}.
InteractionQ16665:HIF1A; NbExp=3; IntAct=EBI-1175354, EBI-447269; P14618-1:PKM; NbExp=2; IntAct=EBI-1175354, EBI-4304679;
SimilarityContains 1 Fe2OG dioxygenase domain. {ECO:0000255|PROSITE-ProRule:PRU00805}.
Subcellular LocationNucleus. Cytoplasm. Note=Colocalizes with WDR83 in the cytoplasm. {ECO:0000250}.
SubunitInteracts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity (By similarity). Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti- apoptotic activity of BCL2. Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex. Interacts with PAX2; the interaction targets PAX2 for destruction. Interacts with PKM; the interaction hydroxylates PKM in hypoxia. {ECO:0000250, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22286099}.
Tissue SpecificityWidely expressed at low levels. Expressed at higher levels in adult heart (cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle), lung and placenta, and in fetal spleen, heart and skeletal muscle. Also expressed in pancreas. Localized to pancreatic acini and islet cells. {ECO:0000269|PubMed:12163023, ECO:0000269|PubMed:12670503, ECO:0000269|PubMed:21575608}.
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