HIF1A
entrez
3091
canonical
uniprot
Q16665
canonical
ensembl
ENSG00000100644
resolver
ensp
ENSP00000323326
resolver
ensp
ENSP00000338018
resolver
ensp
ENSP00000437955
resolver
genesymbol
HIF1A
resolver
genesymbol_syn
BHLHE78
resolver
genesymbol_syn
MOP1
resolver
genesymbol_syn
PASD8
resolver
hgnc
HGNC:4910
resolver
uniprot
C0LZJ3
resolver
uniprot
D0VY79
resolver
uniprot
Q53XP6
resolver
uniprot
Q96PT9
resolver
uniprot
Q9UPB1
resolver
uniprot_entry
D0VY79_HUMAN
resolver
uniprot_entry
HIF1A_HUMAN
resolver
uniprot_sec
C0LZJ3
resolver
uniprot_sec
Q53XP6
resolver
uniprot_sec
Q96PT9
resolver
uniprot_sec
Q9UPB1
resolver
activity_regulation
ACTIVITY REGULATION: Induced by reactive oxygen species (ROS). {ECO:0000269|PubMed:32697943}.; ACTIVITY REGULATION: (Microbial infection) In monocytes, human coronavirus SARS-CoV-2 increases HIF1A levels and activity which promotes a pro-inflammatory state. {ECO:0000269|PubMed:32697943}.
uniprot
proteins
amino_acid_sequence
MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVMRLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYMGLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGRTMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECVLKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTETDDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEPNPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLFAEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVTVFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYRDTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKRKMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
uniprot
proteins
function
FUNCTION: Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:16543236, PubMed:9887100). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298). {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:10594042, ECO:0000269|PubMed:11292861, ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16543236, ECO:0000269|PubMed:16973622, ECO:0000269|PubMed:17610843, ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19528298, ECO:0000269|PubMed:20624928, ECO:0000269|PubMed:22009797, ECO:0000269|PubMed:30125331, ECO:0000269|PubMed:9887100}.; FUNCTION: (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent pro-inflammatory state (PubMed:32697943). In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons (PubMed:32697943). Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response (PubMed:32697943). {ECO:0000269|PubMed:32697943}.
uniprot
proteins
mass_dalton
92670
uniprot
proteins
mutagenesis
MUTAGEN 18; /note="R->K: Strongly reduced GlcNAcylation by E.coli NleB1."; /evidence="ECO:0000269|PubMed:30125331"; MUTAGEN 247; /note="S->A: Constitutive kinase activity."; /evidence="ECO:0000269|PubMed:20699359"; MUTAGEN 247; /note="S->D: Impaired kinase activity."; /evidence="ECO:0000269|PubMed:20699359"; MUTAGEN 377; /note="K->R: No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-391; R-477 and R-532."; /evidence="ECO:0000269|PubMed:17610843"; MUTAGEN 389; /note="K->R: No change in sumoylation."; /evidence="ECO:0000269|PubMed:15465032"; MUTAGEN 391; /note="K->R: Abolishes 1 sumoylation. Abolishes 1 sumoylation; when associated with R-532. Abolishes 2 sumoylations; when associated with R-477. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-477 and R-532."; /evidence="ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:17610843"; MUTAGEN 392; /note="K->R: No change in sumoylation."; /evidence="ECO:0000269|PubMed:15465032"; MUTAGEN 394; /note="P->A: No change in VHLE3-dependent ubiquitination."; /evidence="ECO:0000269|PubMed:11566883"; MUTAGEN 397; /note="L->A: Abolishes VHLE3-dependent ubiquitination; when associated with A-400."; /evidence="ECO:0000269|PubMed:11566883"; MUTAGEN 400; /note="L->A: Abolishes VHLE3-dependent ubiquitination; when associated with A-397."; /evidence="ECO:0000269|PubMed:11566883"; MUTAGEN 402; /note="P->A: Abolishes in VHLE3-dependent ubiquitination, abolishes oxygen-dependent regulation of VP16, partially reduced VHLE target site ubiquitination and no interaction with VHL. No VHLE target site ubiquitination; when associated with G-564. Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-564."; /evidence="ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946"; MUTAGEN 442; /note="K->R: No change in sumoylation."; /evidence="ECO:0000269|PubMed:15465032"; MUTAGEN 460; /note="K->R: No change in sumoylation nor in ARD1-mediated acetylation."; /evidence="ECO:0000269|PubMed:15465032"; MUTAGEN 477; /note="K->R: Abolishes 1 sumoylation. Abolishes 2 sumoylations; when associated with R-391. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-532."; /evidence="ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:17610843"; MUTAGEN 532; /note="K->R: Reduced ubiquitination. No change in sumoylation nor on interaction with NAA10. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-477. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-538 and K-547."; /evidence="ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16288748, ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:17610843"; MUTAGEN 538; /note="K->R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-547."; /evidence="ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16862177"; MUTAGEN 547; /note="K->R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-538."; /evidence="ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16862177"; MUTAGEN 551; /note="S->G: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination."; /evidence="ECO:0000269|PubMed:10758161"; MUTAGEN 552; /note="T->A: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination."; /evidence="ECO:0000269|PubMed:10758161"; MUTAGEN 564; /note="P->A: Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-402."; /evidence="ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946"; MUTAGEN 564; /note="P->G: No change in VHL-dependent ubiquitination. Partially reduced VHLE target site ubiquitination. No VHLE target site ubiquitination; when associated with A-402."; /evidence="ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946"; MUTAGEN 576; /note="S->A: Induces stabilization of the protein."; /evidence="ECO:0000269|PubMed:20889502"; MUTAGEN 657; /note="S->A: Induces stabilization of the protein."; /evidence="ECO:0000269|PubMed:20889502"; MUTAGEN 709; /note="K->R: Abolishes SIRT2-mediated deacetylation, increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation. Increases interaction with EGLN1."; /evidence="ECO:0000269|PubMed:24681946"; MUTAGEN 719; /note="K->T: Dramatic reduction of accumulation in the nucleus in response to hypoxia."; /evidence="ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:9822602"; MUTAGEN 795; /note="L->A: Inhibits interaction with EP300 and transactivation activity."; /evidence="ECO:0000269|PubMed:12778114"; MUTAGEN 800; /note="C->A: Blocks increase in transcriptional activation caused by nitrosylation."; /evidence="ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:12914934"; MUTAGEN 800; /note="C->S: Abolishes hypoxia-inducible transcriptional activation of ctaD."; /evidence="ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:12914934"; MUTAGEN 803; /note="N->A: Recruits CREBBP. No enhancement of CREBBP by Clioquinol in the presence of FIH1. No change in nuclear location nor on repression of transcriptional activity in the presence of histone deacetylase inhibitor."; /evidence="ECO:0000269|PubMed:16543236, ECO:0000269|PubMed:16973622
uniprot
proteins
post_translational_modification
PTM: S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex. {ECO:0000269|PubMed:12560087, ECO:0000269|PubMed:12914934}.; PTM: Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding (PubMed:20699359, PubMed:20889502). Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome (By similarity). {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:20889502}.; PTM: Sumoylated; with SUMO1 under hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation is enhanced through interaction with RWDD3 (PubMed:17956732). Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation (PubMed:15465032, PubMed:15776016, PubMed:17610843). Desumoylation by SENP1 increases its stability amd transcriptional activity (By similarity). There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity (Probable). {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:17610843, ECO:0000269|PubMed:17956732, ECO:0000305}.; PTM: Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation (PubMed:12464182). Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (PubMed:24681946). {ECO:0000269|PubMed:12464182, ECO:0000269|PubMed:24681946}.; PTM: Polyubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803. Ubiquitinated by E3 ligase VHL (PubMed:25615526). Deubiquitinated by UCHL1 (PubMed:25615526). {ECO:0000269|PubMed:12080085, ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:22537386, ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:25974097}.; PTM: In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). EGLN3/PHD3 has also been shown to hydroxylate Pro-564 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Deubiquitinated by USP20 (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, PubMed:25974097). In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation (PubMed:12080085). This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol (PubMed:12080085). Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation (PubMed:28296633). {ECO:0000269|PubMed:11292861, ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:12080085, ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:25974097, ECO:0000269|PubMed:28296633}.; PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains. {ECO:0000269|PubMed:12080085}.; PTM: (Microbial infection) Glycosylated at Arg-18 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation enhances transcription factor activity and impairs glucose metabolism. {ECO:0000269|PubMed:30125331}.
uniprot
proteins
pubmed
10202154
uniprot
proteins
pubmed
10594042
uniprot
proteins
pubmed
10758161
uniprot
proteins
pubmed
10944113
uniprot
proteins
pubmed
11006129
uniprot
proteins
pubmed
11089639
uniprot
proteins
pubmed
11292861
uniprot
proteins
pubmed
11389899
uniprot
proteins
pubmed
11566883
uniprot
proteins
pubmed
11959977
uniprot
proteins
pubmed
11959990
uniprot
proteins
pubmed
12004076
uniprot
proteins
pubmed
12050673
uniprot
proteins
pubmed
12080085
uniprot
proteins
pubmed
12351678
uniprot
proteins
pubmed
12446723
uniprot
proteins
pubmed
12464182
uniprot
proteins
pubmed
12508121
uniprot
proteins
pubmed
12560087
uniprot
proteins
pubmed
12778114
uniprot
proteins
pubmed
12914934
uniprot
proteins
pubmed
14757845
uniprot
proteins
pubmed
15465032
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15776016
uniprot
proteins
pubmed
16288748
uniprot
proteins
pubmed
16543236
uniprot
proteins
pubmed
16862177
uniprot
proteins
pubmed
16973622
uniprot
proteins
pubmed
17244529
uniprot
proteins
pubmed
17610843
uniprot
proteins
pubmed
17956732
uniprot
proteins
pubmed
18638657
uniprot
proteins
pubmed
18658046
uniprot
proteins
pubmed
18809331
uniprot
proteins
pubmed
19046997
uniprot
proteins
pubmed
19528298
uniprot
proteins
pubmed
20624928
uniprot
proteins
pubmed
20699359
uniprot
proteins
pubmed
20889502
uniprot
proteins
pubmed
22009797
uniprot
proteins
pubmed
22128162
uniprot
proteins
pubmed
22286099
uniprot
proteins
pubmed
22537386
uniprot
proteins
pubmed
23401859
uniprot
proteins
pubmed
23469069
uniprot
proteins
pubmed
24681946
uniprot
proteins
pubmed
25615526
uniprot
proteins
pubmed
25974097
uniprot
proteins
pubmed
26517842
uniprot
proteins
pubmed
28296633
uniprot
proteins
pubmed
30125331
uniprot
proteins
pubmed
32697943
uniprot
proteins
pubmed
7539918
uniprot
proteins
pubmed
8917528
uniprot
proteins
pubmed
9079689
uniprot
proteins
pubmed
9235919
uniprot
proteins
pubmed
9653127
uniprot
proteins
pubmed
9782081
uniprot
proteins
pubmed
9822602
uniprot
proteins
pubmed
9887100
uniprot
proteins
sequence_length
826
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9822602}. Nucleus {ECO:0000269|PubMed:22009797, ECO:0000269|PubMed:9822602}. Nucleus speckle {ECO:0000250|UniProtKB:Q61221}. Note=Colocalizes with HIF3A in the nucleus and speckles (By similarity). Cytoplasmic in normoxia, nuclear translocation in response to hypoxia (PubMed:9822602). {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:9822602}.
uniprot
proteins