EGLN3 Gene (PHD3): Function, Mutations, and Disease Associations | Biomedical Resource

EGLN3 (egl-9 family hypoxia-inducible factor 3), also known as PHD3, encodes a prolyl hydroxylase that acts as a cellular oxygen sensor. Under normoxic conditions, EGLN3 hydroxylates specific proline residues on hypoxia-inducible factor (HIF) alpha subunits, targeting them for proteasomal degradation via the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Under hypoxia, EGLN3 activity is reduced, allowing HIF-alpha to accumulate and activate transcription of genes involved in angiogenesis, metabolism, and cell survival. EGLN3 also has HIF-independent functions, including roles in apoptosis, neuronal development, and regulation of cell proliferation. Aberrant EGLN3 expression or function has been implicated in various cancers, cardiovascular diseases, and metabolic disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• HIF-1-alpha transcription factor network

• Oxygen-dependent proline hydroxylation of HIF-alpha

• VHL-mediated degradation of HIF-alpha

• Hypoxia response pathway

EGLN3 (PHD3) is a 239-amino acid protein (UniProt Q9H6Z9) belonging to the iron(II)- and 2-oxoglutarate-dependent dioxygenase family. It contains a conserved catalytic domain that hydroxylates proline residues (Pro564) on HIF-alpha subunits. The protein is primarily cytoplasmic but can translocate to the nucleus under certain conditions. EGLN3 has a longer half-life than other PHDs and is itself regulated by hypoxia and growth factors. Beyond HIF regulation, EGLN3 interacts with multiple partners (e.g., ATF4, IKKβ) to modulate apoptosis, inflammation, and metabolism.