EGLN3_MOUSE
ID EGLN3_MOUSE Reviewed; 239 AA.
AC Q91UZ4; Q3TCG8; Q8C8M6; Q8CCA8; Q8R5C7;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Prolyl hydroxylase EGLN3 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000305|PubMed:24809345};
DE AltName: Full=Egl nine homolog 3;
DE EC=1.14.11.29 {ECO:0000250|UniProtKB:Q9H6Z9};
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 3;
DE Short=HIF-PH3;
DE Short=HIF-prolyl hydroxylase 3;
DE Short=HPH-3;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 3 {ECO:0000303|PubMed:18332118};
DE Short=PHD3 {ECO:0000303|PubMed:18332118};
DE AltName: Full=SM-20 {ECO:0000303|PubMed:10543731};
GN Name=Egln3 {ECO:0000303|PubMed:19584355, ECO:0000312|MGI:MGI:1932288};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RC TISSUE=Embryo;
RX PubMed=10543731;
RA Moschella M.C., Menzies K., Tsao L., Lieb M.A., Kohtz J.D., Kohtz D.S.,
RA Taubman M.B.;
RT "SM-20 is a novel growth factor-responsive gene regulated during skeletal
RT muscle development and differentiation.";
RL Gene Expr. 8:59-66(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11574160; DOI=10.1016/s0378-1119(01)00633-3;
RA Taylor M.S.;
RT "Characterization and comparative analysis of the EGLN gene family.";
RL Gene 275:125-132(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Dendritic cell, Lung, and Retina;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N-3, and NMRI; TISSUE=Mammary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=12234095; DOI=10.1139/o02-115;
RA Lieb M.E., Menzies K., Moschella M.C., Ni R., Taubman M.B.;
RT "Mammalian EGLN genes have distinct patterns of mRNA expression and
RT regulation.";
RL Biochem. Cell Biol. 80:421-426(2002).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=18332118; DOI=10.1128/mcb.02041-07;
RA Bishop T., Gallagher D., Pascual A., Lygate C.A., de Bono J.P.,
RA Nicholls L.G., Ortega-Saenz P., Oster H., Wijeyekoon B., Sutherland A.I.,
RA Grosfeld A., Aragones J., Schneider M., van Geyte K., Teixeira D.,
RA Diez-Juan A., Lopez-Barneo J., Channon K.M., Maxwell P.H., Pugh C.W.,
RA Davies A.M., Carmeliet P., Ratcliffe P.J.;
RT "Abnormal sympathoadrenal development and systemic hypotension in PHD3-/-
RT mice.";
RL Mol. Cell. Biol. 28:3386-3400(2008).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=19720742; DOI=10.1128/mcb.00331-09;
RA Minamishima Y.A., Moslehi J., Padera R.F., Bronson R.T., Liao R.,
RA Kaelin W.G. Jr.;
RT "A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian
RT hypoxic response in vivo.";
RL Mol. Cell. Biol. 29:5729-5741(2009).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=19584355; DOI=10.1126/scisignal.2000444;
RA Xie L., Xiao K., Whalen E.J., Forrester M.T., Freeman R.S., Fong G.,
RA Gygi S.P., Lefkowitz R.J., Stamler J.S.;
RT "Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and
RT ubiquitylation by pVHL.";
RL Sci. Signal. 2:RA33-RA33(2009).
RN [9]
RP FUNCTION, AND INDUCTION.
RX PubMed=21317538; DOI=10.1172/jci43273;
RA Walmsley S.R., Chilvers E.R., Thompson A.A., Vaughan K., Marriott H.M.,
RA Parker L.C., Shaw G., Parmar S., Schneider M., Sabroe I., Dockrell D.H.,
RA Milo M., Taylor C.T., Johnson R.S., Pugh C.W., Ratcliffe P.J.,
RA Maxwell P.H., Carmeliet P., Whyte M.K.;
RT "Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of
RT neutrophilic inflammation in humans and mice.";
RL J. Clin. Invest. 121:1053-1063(2011).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND UBIQUITINATION.
RX PubMed=24809345; DOI=10.1371/journal.pgen.1004348;
RA Scortegagna M., Kim H., Li J.L., Yao H., Brill L.M., Han J., Lau E.,
RA Bowtell D., Haddad G., Kaufman R.J., Ronai Z.A.;
RT "Fine tuning of the UPR by the ubiquitin ligases Siah1/2.";
RL PLoS Genet. 10:e1004348-e1004348(2014).
CC -!- FUNCTION: Prolyl hydroxylase that mediates hydroxylation of proline
CC residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A
CC (PubMed:24809345). Target proteins are preferentially recognized via a
CC LXXLAP motif (By similarity). Cellular oxygen sensor that catalyzes,
CC under normoxic conditions, the post-translational formation of 4-
CC hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (By
CC similarity). Hydroxylates a specific proline found in each of the
CC oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-
CC terminal, CODD) of HIF1A (By similarity). Also hydroxylates HIF2A (By
CC similarity). Has a preference for the CODD site for both HIF1A and
CC HIF2A (By similarity). Hydroxylation on the NODD site by EGLN3 appears
CC to require prior hydroxylation on the CODD site (By similarity).
CC Hydroxylated HIFs are then targeted for proteasomal degradation via the
CC von Hippel-Lindau ubiquitination complex (By similarity). Under hypoxic
CC conditions, the hydroxylation reaction is attenuated allowing HIFs to
CC escape degradation resulting in their translocation to the nucleus,
CC heterodimerization with HIF1B, and increased expression of hypoxy-
CC inducible genes (By similarity). ELGN3 is the most important isozyme in
CC limiting physiological activation of HIFs (particularly HIF2A) in
CC hypoxia (By similarity). Also hydroxylates PKM in hypoxia, limiting
CC glycolysis (By similarity). Under normoxia, hydroxylates and regulates
CC the stability of ADRB2. Regulator of cardiomyocyte and neuronal
CC apoptosis (By similarity). In cardiomyocytes, inhibits the anti-
CC apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex (By
CC similarity). In neurons, has a NGF-induced proapoptotic effect,
CC probably through regulating CASP3 activity (By similarity). Also
CC essential for hypoxic regulation of neutrophilic inflammation
CC (PubMed:21317538). Plays a crucial role in DNA damage response (DDR) by
CC hydroxylating TELO2, promoting its interaction with ATR which is
CC required for activation of the ATR/CHK1/p53 pathway (By similarity).
CC Also mediates hydroxylation of ATF4, leading to decreased protein
CC stability of ATF4 (PubMed:24809345). {ECO:0000250|UniProtKB:Q9H6Z9,
CC ECO:0000269|PubMed:21317538, ECO:0000269|PubMed:24809345}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[protein] + O2 = CO2 + succinate +
CC trans-4-hydroxy-L-prolyl-[protein]; Xref=Rhea:RHEA:63484, Rhea:RHEA-
CC COMP:12408, Rhea:RHEA-COMP:16354, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965;
CC Evidence={ECO:0000305|PubMed:24809345};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63485;
CC Evidence={ECO:0000305|PubMed:24809345};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[hypoxia-inducible factor alpha
CC subunit] + O2 = CO2 + succinate + trans-4-hydroxy-L-prolyl-[hypoxia-
CC inducible factor alpha subunit]; Xref=Rhea:RHEA:48400, Rhea:RHEA-
CC COMP:12093, Rhea:RHEA-COMP:12094, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965; EC=1.14.11.29;
CC Evidence={ECO:0000250|UniProtKB:Q9H6Z9};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00805};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000250|UniProtKB:Q96KS0};
CC -!- SUBUNIT: Interacts with ADRB2; the interaction hydroxylates ADRB2
CC facilitating its ubiquitination by the VHL-E3 ligase complex (By
CC similarity). Interacts with PKM; the interaction hydroxylates PKM in
CC hypoxia (By similarity). Interacts with WDR83; the interaction leads to
CC almost complete elimination of HIF-mediated reporter activity (By
CC similarity). Interacts with BCL2 (via its BH4 domain); the interaction
CC disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of
CC BCL2 (By similarity). Interacts with LIMD1, WTIP and AJUBA (By
CC similarity). {ECO:0000250|UniProtKB:Q62630,
CC ECO:0000250|UniProtKB:Q9H6Z9}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9H6Z9}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9H6Z9}. Note=Colocalizes with WDR83 in the
CC cytoplasm. {ECO:0000250|UniProtKB:Q62630}.
CC -!- TISSUE SPECIFICITY: Highly expressed in cardiac and smooth muscle. Also
CC high expression in brain, skeletal muscle and kidney. Low levels in
CC lung. {ECO:0000269|PubMed:12234095}.
CC -!- DEVELOPMENTAL STAGE: Detected at 8.5 dpc in proliferating myoblasts of
CC the dermomyotome and the developing heart tube. From dermomyotomal
CC cells of the rostral somites expression progressed in a rostral to
CC caudal pattern, with highest levels seen in the muscle primordia and
CC mature muscles. {ECO:0000269|PubMed:10543731}.
CC -!- INDUCTION: Induced by hypoxia. Up-regulated in proliferating myoblasts
CC induced to form differentiated myotubes. {ECO:0000269|PubMed:21317538}.
CC -!- DOMAIN: The Beta(2)beta(3) 'finger-like' loop domain is important for
CC substrate (HIFs' CODD/NODD) selectivity.
CC {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- PTM: Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded
CC protein response (UPR), leading to its degradation.
CC {ECO:0000269|PubMed:24809345}.
CC -!- DISRUPTION PHENOTYPE: Null mice exhibit reduced apoptosis of in
CC sympathetic neurons. However, the sympathoadrenal system appears
CC hypofunctional with reduced target tissue innervation, adrenal
CC medullary secretory capacity, sympathoadrenal responses, and systemic
CC blood pressure. There is an increase in ADRB2 abundance and decrease of
CC ADRB1 abundance in heart. {ECO:0000269|PubMed:18332118,
CC ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:19720742}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH22961.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF421882; AAL17824.1; -; mRNA.
DR EMBL; AJ310548; CAC42517.1; -; mRNA.
DR EMBL; AK044787; BAC32092.1; -; mRNA.
DR EMBL; AK165972; BAE38492.1; -; mRNA.
DR EMBL; AK170732; BAE41988.1; -; mRNA.
DR EMBL; BC022961; AAH22961.1; ALT_INIT; mRNA.
DR EMBL; BC044926; AAH44926.1; -; mRNA.
DR EMBL; BC058278; AAH58278.1; -; mRNA.
DR EMBL; BC069893; AAH69893.1; -; mRNA.
DR CCDS; CCDS25908.1; -.
DR RefSeq; NP_082409.2; NM_028133.2.
DR AlphaFoldDB; Q91UZ4; -.
DR SMR; Q91UZ4; -.
DR BioGRID; 227483; 4.
DR STRING; 10090.ENSMUSP00000041874; -.
DR PhosphoSitePlus; Q91UZ4; -.
DR MaxQB; Q91UZ4; -.
DR PaxDb; Q91UZ4; -.
DR PeptideAtlas; Q91UZ4; -.
DR PRIDE; Q91UZ4; -.
DR ProteomicsDB; 277804; -.
DR DNASU; 112407; -.
DR GeneID; 112407; -.
DR KEGG; mmu:112407; -.
DR UCSC; uc007nns.2; mouse.
DR CTD; 112399; -.
DR MGI; MGI:1932288; Egln3.
DR eggNOG; KOG3710; Eukaryota.
DR InParanoid; Q91UZ4; -.
DR OrthoDB; 1604981at2759; -.
DR PhylomeDB; Q91UZ4; -.
DR TreeFam; TF314595; -.
DR BRENDA; 1.14.11.29; 3474.
DR Reactome; R-MMU-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR BioGRID-ORCS; 112407; 2 hits in 76 CRISPR screens.
DR ChiTaRS; Egln3; mouse.
DR PRO; PR:Q91UZ4; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q91UZ4; protein.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:MGI.
DR GO; GO:0008198; F:ferrous iron binding; IBA:GO_Central.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; ISO:MGI.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; IDA:MGI.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEP:MGI.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; ISO:MGI.
DR GO; GO:0018126; P:protein hydroxylation; ISS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IMP:UniProtKB.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR InterPro; IPR044862; Pro_4_hyd_alph_FE2OG_OXY.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cytoplasm; Dioxygenase; DNA damage; Iron; Metal-binding;
KW Nucleus; Oxidoreductase; Reference proteome; Ubl conjugation; Vitamin C.
FT CHAIN 1..239
FT /note="Prolyl hydroxylase EGLN3"
FT /id="PRO_0000206667"
FT DOMAIN 116..214
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 62..73
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT REGION 88..104
FT /note="Required for interaction with ADRB2"
FT /evidence="ECO:0000250|UniProtKB:Q9H6Z9"
FT BINDING 135
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 137
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 196
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 205
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT CONFLICT 65
FT /note="R -> C (in Ref. 3; BAC32092/BAE38492/BAE41988)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 239 AA; 27302 MW; F4102753C6498DE5 CRC64;
MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL HYNGALRDGQ
LAGPRAGVSK RHLRGDQITW IGGNEEGCEA INFLLSLIDR LVLYCGSRLG KYYVKERSKA
MVACYPGNGT GYVRHVDNPN GDGRCITCIY YLNKNWDAKL HGGVLRIFPE GKSFVADVEP
IFDRLLFFWS DRRNPHEVQP SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD
