EGLN1

The protein encoded by this gene catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. This protein functions as a cellular oxygen sensor, and under normal oxygen concentration, modification by prolyl hydroxylation is a key regulatory event that targets HIF subunits for proteasomal destruction via the von Hippel-Lindau ubiquitylation complex. Mutations in this gene are associated with erythrocytosis familial type 3 (ECYT3). [provided by RefSeq, Nov 2009]

Full Name

Egl-9 Family Hypoxia Inducible Factor 1

Research Area

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 HIF1B. 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. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.

Biological Process

Cellular response to hypoxia Source: GO_Central
Negative regulation of cyclic-nucleotide phosphodiesterase activity Source: BHF-UCL
Negative regulation of DNA-binding transcription factor activity Source: HGNC-UCL
Oxygen homeostasis Source: HGNC-UCL
Peptidyl-proline hydroxylation to 4-hydroxy-L-proline Source: FlyBase
Regulation of angiogenesis Source: UniProtKB
Response to hypoxia Source: HGNC-UCL
Response to nitric oxide Source: UniProtKB

Cellular Location

Nucleus; Cytoplasm. Mainly cytoplasmic. Shuttles between the nucleus and cytoplasm (PubMed:19631610). Nuclear export requires functional XPO1.

Involvement in disease

Erythrocytosis, familial, 3 (ECYT3):
An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels.

PTM

S-nitrosylation inhibits the enzyme activity up to 60% under aerobic conditions. Chelation of Fe2+ has no effect on the S-nitrosylation. It is uncertain whether nitrosylation occurs on Cys-323 or Cys-326.