EGLN3
EGLN3 (egl-9 family hypoxia inducible factor 3, also known as PHD3 or HIFPH3) is a prolyl hydroxylase that acts as a cellular oxygen sensor. It hydroxylates proline residues in hypoxia-inducible factor alpha proteins and other substrates, marking them for regulation or degradation. Browse Assay Genie's current range of EGLN3 research reagents below, or read on for the biology behind the target.
EGLN3 is a prolyl hydroxylase that hydroxylates proline residues in target proteins, including PKM, TELO2, ATF4, GPX4 and HIF1A. Substrates are preferentially recognised through a LXXLAP motif. Under normoxic conditions, EGLN3 catalyses the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins, acting as a cellular oxygen sensor. It modifies a proline in each oxygen-dependent degradation domain of HIF1A (NODD and CODD) and also hydroxylates HIF2A, with a preference for the CODD site. Hydroxylation of the NODD site appears to require prior hydroxylation of the CODD site.
Hydroxylated HIFs are targeted for proteasomal degradation through the von Hippel-Lindau ubiquitination complex. In hypoxia the reaction is attenuated, so HIFs escape degradation, translocate to the nucleus, heterodimerise with HIF1B and increase expression of hypoxia-inducible genes. EGLN3 is described as the most important isozyme in limiting physiological activation of HIFs, particularly HIF2A, in hypoxia. The EGLN3 protein is found in the nucleus and cytoplasm, and the EGLN3 gene belongs to the Egl-9 family of hypoxia inducible factors, alongside EGLN1 and EGLN2.
Beyond HIF regulation, EGLN3 inhibits ferroptosis by hydroxylating GPX4, which prevents GPX4 degradation by chaperone-mediated autophagy; this is promoted by PSAT1, which supplies the 2-oxoglutarate substrate. In hypoxia it hydroxylates PKM and limits glycolysis, and in normoxia it hydroxylates ADRB2 and regulates its stability. EGLN3 regulates apoptosis in cardiomyocytes, where it disrupts the BAX-BCL2 complex, and in neurons, where it has an NGF-induced proapoptotic effect. It is also essential for hypoxic regulation of neutrophilic inflammation, supports the DNA damage response by hydroxylating TELO2 to promote its interaction with ATR, and destabilises ATF4 through hydroxylation. EGLN3 is implicated in renal cell carcinoma and is a biomarker of clear cell renal cell carcinoma. It was formerly named egl nine homolog 3 (C. elegans).
EGLN3 hydroxylates HIF1A and HIF2A under normoxia and is the key isozyme limiting HIF2A activation in hypoxia.
EGLN3 hydroxylates GPX4 to prevent its degradation by chaperone-mediated autophagy, making it an inhibitor of ferroptosis.
EGLN3 is implicated in renal cell carcinoma and serves as a biomarker of clear cell renal cell carcinoma.
EGLN3 regulates cardiomyocyte and neuronal apoptosis and supports ATR/CHK1/p53 activation through TELO2 hydroxylation.
EGLN3 is a prolyl hydroxylase and cellular oxygen sensor. Under normoxia it hydroxylates HIF1A and HIF2A, targeting them for degradation via the von Hippel-Lindau complex. It also hydroxylates GPX4, PKM, TELO2, ATF4 and ADRB2, linking oxygen sensing to ferroptosis, metabolism and DNA damage response.
EGLN3 is also called PHD3 and HIFPH3, and its full name is egl-9 family hypoxia inducible factor 3. UniProt names the protein prolyl hydroxylase EGLN3. An earlier name was egl nine homolog 3 (C. elegans). It belongs to the Egl-9 family of hypoxia inducible factors.
Orthologues exist in mouse and rat, both named Egln3, so the target can be studied in common model systems; check the datasheet of any product for its validated reactivity. EGLN3 is implicated in renal cell carcinoma and is a biomarker of clear cell renal cell carcinoma.
Other members of the Egl-9 family of hypoxia inducible factor prolyl hydroxylases with products at Assay Genie.
Gene and protein annotations from HGNC, NCBI Gene and UniProt Q9H6Z9; product specifications from Assay Genie datasheets.