InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: EGLN3

Summary

InnateDB Protein

IDBP-4517.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

EGLN3

Protein Name

egl nine homolog 3 (C. elegans)

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000250457

InnateDB Gene

IDBG-4515 (EGLN3)

Protein Structure

UniProt Annotation

Function

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. 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:0000269PubMed:11595184, ECO:0000269PubMed:12181324, ECO:0000269PubMed:16098468, ECO:0000269PubMed:19584355, ECO:0000269PubMed:20849813, ECO:0000269PubMed:20978507, ECO:0000269PubMed:21317538, ECO:0000269PubMed:21483450, ECO:0000269PubMed:21575608, ECO:0000269PubMed:21620138, ECO:0000269PubMed:22797300}.

Subcellular Localization

Nucleus. Cytoplasm. Note=Colocalizes with WDR83 in the cytoplasm. {ECO:0000250}.

Disease Associations

Tissue Specificity

Widely 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:0000269PubMed:12163023, ECO:0000269PubMed:12670503, ECO:0000269PubMed:21575608}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 44 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Experimentally validated
Total	44 [view]
Protein-Protein	44 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005506	iron ion binding
GO:0005515	protein binding
GO:0016491	oxidoreductase activity
GO:0016705	oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
GO:0016706	oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors
GO:0031418	L-ascorbic acid binding
GO:0031545	peptidyl-proline 4-dioxygenase activity

Biological Process

GO:0001666	response to hypoxia
GO:0006915	apoptotic process
GO:0006919	activation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0006974	cellular response to DNA damage stimulus
GO:0018126	protein hydroxylation
GO:0018401	peptidyl-proline hydroxylation to 4-hydroxy-L-proline
GO:0042127	regulation of cell proliferation
GO:0043523	regulation of neuron apoptotic process
GO:0055114	oxidation-reduction process
GO:0061418	regulation of transcription from RNA polymerase II promoter in response to hypoxia
GO:0071456	cellular response to hypoxia