EGLN2

The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene. [provided by RefSeq, Feb 2011]

Full Name

Egl-9 Family Hypoxia Inducible Factor 2

Research Area

Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A (PubMed:11595184, PubMed:12039559, PubMed:15925519, PubMed:16509823, PubMed:17114296, PubMed:23932902).

Target proteins are preferentially recognized via a LXXLAP motif (PubMed:11595184, PubMed:12039559, PubMed:15925519).

Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519, PubMed:19339211).

Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519).

Also hydroxylates HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519).

Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519).

Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12039559, PubMed:15925519).

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 (PubMed:11595184, PubMed:12039559, PubMed:15925519).

EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle (PubMed:11595184, PubMed:12039559, PubMed:15925519).

Also regulates susceptibility to normoxic oxidative neuronal death (PubMed:11595184, PubMed:12039559, PubMed:15925519).

Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation (PubMed:23932902).

Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions (PubMed:17114296).

Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).

Biological Process

Cell redox homeostasis Source: UniProtKB
Cellular response to hypoxia Source: GO_Central
Intracellular estrogen receptor signaling pathway Source: UniProtKB
Peptidyl-proline hydroxylation to 4-hydroxy-L-proline Source: UniProtKB
Positive regulation of protein catabolic process Source: UniProtKB
Regulation of cell growth Source: UniProtKB
Regulation of neuron apoptotic process Source: UniProtKB
Response to hypoxia Source: UniProtKB

Cellular Location

Nucleus

PTM

Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded protein response (UPR), leading to its degradation.