Heme oxygenase 1 (HO-1 / HSP32) is the rate-limiting enzyme of heme catabolism. It is a tail-anchored, single-pass type IV endoplasmic reticulum membrane protein whose catalytic domain faces the cytosol. Using molecular oxygen and electrons donated by NADPH--cytochrome P450 reductase, it oxidatively cleaves the alpha-methene bridge of heme b to produce biliverdin IX-alpha, carbon monoxide (CO), and free ferrous iron (Fe2+); biliverdin is subsequently reduced to bilirubin by biliverdin reductase. HO-1 is a highly inducible cytoprotective, antioxidant and anti-inflammatory stress-response enzyme, strongly upregulated by its heme substrate and by oxidative stress, heavy metals, hypoxia and UVA, largely through the NRF2 (NFE2L2)-KEAP1/antioxidant response element pathway. Its cytoprotective actions are mediated by its reaction products: the bilirubin/biliverdin antioxidant system, CO signaling, and sequestration of released iron into ferritin. HO-1 forms homodimers/oligomers via its C-terminal transmembrane anchor, which is required for stability and activity in the ER. In humans, loss of HMOX1 causes heme oxygenase 1 deficiency, a severe systemic disorder with intravascular hemolysis, erythrocyte fragmentation, endothelial injury and tissue iron deposition.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004392 heme oxygenase (decyclizing) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of HMOX1, supported phylogenetically and by direct human biochemistry. This is the rate-limiting activity of heme catabolism. Reason: Heme oxygenase activity is the defining, experimentally validated function of HMOX1 (also directly demonstrated in PMID:7703255, PMID:11121422, PMID:17915953). IBA correctly propagates it across the heme oxygenase family. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HMOX1 is an ER-anchored enzyme, so the ER is a correct location. The more specific and better-supported location is the ER membrane. Reason: Correct but less specific than endoplasmic reticulum membrane (GO:0005789), which is the experimentally supported core location. Retained as non-core. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Plasma membrane is not a substantiated location for human HO-1, which is an ER tail-anchored protein. This IBA likely reflects a family-tree over-propagation. Reason: No experimental support for HMOX1 acting at the plasma membrane in human; the enzyme is ER membrane-anchored (PubMed:19556236, 22419571, 27184847). Left as non-core rather than removed (IBA), but it should not be treated as a real HO-1 location. |
| GO:0006979 response to oxidative stress | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HO-1 is a canonical oxidative-stress-response enzyme; its induction and products protect cells from oxidative injury. Reason: A genuine, well-established downstream physiological role (also IMP in PMID:9884342), but a consequence of the heme oxygenase reaction rather than the core molecular function. |
| GO:0020037 heme binding | IBA GO_REF:0000033 | ACCEPT | Summary: Heme is the substrate/cofactor of HO-1; heme binding is a core, experimentally validated molecular function. Reason: Heme-binding residues are crystallographically resolved (PubMed:12842469) and binding is directly characterized (PMID:17915953). Required for catalysis. |
| GO:0042167 heme catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process: HMOX1 catalyzes the rate-limiting step of heme catabolism. Reason: Directly supported by human biochemistry (PMID:7703255, PMID:17915953) and appropriately propagated by IBA. |
| GO:0006788 heme oxidation | IBA GO_REF:0000033 | ACCEPT | Summary: HO-1 oxidatively cleaves the heme ring; heme oxidation is a correct direct process term. Reason: Represents the oxidative chemistry of the core catalytic activity; also IDA in PMID:17915953. |
| GO:0004392 heme oxygenase (decyclizing) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the core catalytic activity via InterPro/EC/Rhea; correct. Reason: Consistent with the experimentally validated core function and the EC 1.14.14.18 / RHEA:21764 catalytic reaction in UniProt. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct core location, derived from the UniProt Subcellular Location vocabulary mapping. Reason: HMOX1 is a tail-anchored ER membrane protein; multiple experimental annotations agree (PubMed:19556236, 22419571, 27184847). |
| GO:0006788 heme oxidation | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO assignment of heme oxidation from the heme oxygenase domain; correct. Reason: Matches the core catalytic chemistry and the InterPro heme oxygenase signatures. |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a high-throughput YFP-complementation telomere-signaling screen (interaction with POT1). Uninformative for HO-1 molecular function. Reason: Generic protein binding from an HTP interactome screen; not indicative of a specific HO-1 molecular function and no defined biological role for a HO-1/POT1 interaction. Retained (IPI) but flagged as over-annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from the HuRI reference binary interactome (many ER/membrane partners). Uninformative for HO-1 function. Reason: High-throughput systematic Y2H-style mapping; the numerous membrane-protein partners largely reflect co-membership in ER/membrane compartments rather than a specific HO-1 molecular function. |
| GO:0005515 protein binding | IPI PMID:32353859 A SARS-CoV-2 protein interaction map reveals targets for dru... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a SARS-CoV-2 host-interactome map (ORF3a). Non-specific. Reason: The HMOX1-ORF3a host-virus interaction is documented (see PMID:35239449), but the bare protein binding term is uninformative; captured better as a host-virus interaction note. |
| GO:0005515 protein binding | IPI PMID:32838362 Virus-Host Interactome and Proteomic Survey Reveal Potential... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a virus-host interactome/proteomic survey (ORF3a). Non-specific. Reason: High-throughput host-virus interaction mapping; uninformative bare protein binding. |
| GO:0005515 protein binding | IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a comparative coronavirus host-interactome network (ORF3a). Non-specific. Reason: High-throughput host-virus interactome; uninformative bare protein binding. |
| GO:0005515 protein binding | IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a comprehensive SARS-CoV-2-human interactome (ORF3a). Non-specific. Reason: High-throughput host-virus interactome; uninformative bare protein binding. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear localization by Ensembl orthology transfer from mouse. HO-1 nuclear translocation of a cleaved fragment is reported under stress, but this is a secondary sub-pool. Reason: Nuclear HO-1 is a context/stress-dependent sub-pool of a proteolytically processed form, not the enzyme's primary location. Kept as non-core. |
| GO:0004392 heme oxygenase (decyclizing) activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of the core catalytic activity from mouse Hmox1; correct. Reason: Redundant with the directly demonstrated human activity; consistent and correct. |
| GO:1900016 negative regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Anti-inflammatory role transferred by similarity from mouse Hmox1. Consistent with HO-1 being anti-inflammatory, but a downstream physiological consequence. Reason: Genuine downstream effect of HO-1 products (CO, bilirubin) on inflammation, but not the core molecular function; ISS-based. |
| GO:0110076 negative regulation of ferroptosis | IMP PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against fe... | KEEP AS NON CORE | Summary: Knockdown of HO-1 (with NQO1 and FTH1), an NRF2 target, promoted ferroptosis in HCC cells, supporting a protective role. Reason: A downstream cytoprotective consequence of HO-1 (via iron handling/antioxidant products), not the core molecular function. Note HO-1 can be context-dependent for ferroptosis, but the cited experiment supports protection. Supporting Evidence: PMID:26403645 Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. |
| GO:0042167 heme catabolic process | IDA PMID:7703255 Expression and characterization of truncated human heme oxyg... | ACCEPT | Summary: Direct demonstration that human HO-1 converts heme to biliverdin, defining its role in heme catabolism. Core process. Reason: Truncated hHO-1 reconstituted with cytochrome P450 reductase converts heme to biliverdin. Supporting Evidence: PMID:7703255 The purified, truncated hHO-1/heme complex is spectroscopically indistinguishable from that of the rat enzyme and converts heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase. |
| GO:0006357 regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: HO-1 is an enzyme, not a transcription factor. This ISS (transferred from rat P06762) likely over-interprets nuclear-translocation observations. Reason: There is no robust evidence that HO-1 directly regulates RNA polymerase II transcription; any nuclear role is indirect/context-specific. Over-annotation via similarity transfer. |
| GO:0005789 endoplasmic reticulum membrane | IMP PMID:19556236 Oligomerization is crucial for the stability and function of... | ACCEPT | Summary: Experimental support that HO-1 resides and functions in the ER membrane, with oligomerization via its transmembrane segment. Core location. Reason: HO-1 is anchored in the ER by a single C-terminal transmembrane segment; oligomerization is required for stability/function there. Supporting Evidence: PMID:19556236 a stress-inducible enzyme anchored in the endoplasmic reticulum (ER) by a single transmembrane segment (TMS) located at the C terminus |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:27184847 APEX Fingerprinting Reveals the Subcellular Localization of ... | ACCEPT | Summary: APEX proximity fingerprinting confirmed the ER membrane localization and membrane topology of HMOX1. Core location. Reason: Directly determined membrane protein topology of HMOX1 by APEX labeling. Supporting Evidence: PMID:27184847 successfully elucidated the membrane protein topology of HMOX1 |
| GO:0006879 intracellular iron ion homeostasis | IDA PMID:17915953 Expression and characterization of full-length human heme ox... | KEEP AS NON CORE | Summary: HO-1 releases free iron during heme degradation, contributing to cellular iron handling. Reason: A downstream consequence of the heme oxygenase reaction (release of Fe2+ and rerouting to ferritin), not the core molecular function. Supporting Evidence: PMID:17915953 HO-1 receives the electrons necessary for catalysis from the flavoprotein NADPH cytochrome P450 reductase (CPR), releasing free iron and carbon monoxide. |
| GO:0060586 multicellular organismal-level iron ion homeostasis | IMP PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | KEEP AS NON CORE | Summary: Human HO-1 deficiency causes systemic iron deposition and dysregulated iron handling, supporting a role in organism-level iron homeostasis. Reason: An organism-level physiological consequence of losing heme catabolism, downstream of the core enzymatic function. Supporting Evidence: PMID:9884342 Iron deposition was noted in renal and hepatic tissue. |
| GO:0005515 protein binding | IPI PMID:35239449 SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulop... | MARK AS OVER ANNOTATED | Summary: Bare protein binding capturing the HMOX1-SARS-CoV-2 ORF3a interaction. The interaction is real but the term is uninformative. Reason: HMOX1 interacts with ORF3a and promotes ORF3a-induced autophagy (documented in UniProt), but bare protein binding does not convey an informative HO-1 molecular function. |
| GO:0050728 negative regulation of inflammatory response | ISS PMID:11447290 Targeted expression of heme oxygenase-1 prevents the pulmona... | KEEP AS NON CORE | Summary: Anti-inflammatory role transferred by similarity from rat Hmox1 (protection against hypoxic pulmonary inflammation). Reason: A genuine downstream anti-inflammatory effect of HO-1 activity/products, not the core molecular function; ISS-based. |
| GO:0004392 heme oxygenase (decyclizing) activity | IMP PMID:11121422 Disruption of an active site hydrogen bond converts human he... | ACCEPT | Summary: Mutagenesis of active-site Asp-140 abolishes heme oxygenase activity, directly confirming the catalytic function. Core. Reason: D140A/F/L/H/N mutants lose heme oxygenase (biliverdin-forming) activity, establishing the catalytic role of the residue and the enzyme. Supporting Evidence: PMID:11121422 The D140A, D140H, and D140N mutants retain a trace (<3%) of biliverdin forming activity, but the D140F and D140L mutants are inactive in this respect. |
| GO:0004392 heme oxygenase (decyclizing) activity | IDA PMID:7703255 Expression and characterization of truncated human heme oxyg... | ACCEPT | Summary: Direct biochemical demonstration of human heme oxygenase activity (heme to biliverdin). Core molecular function. Reason: Purified human HO-1 converts heme to biliverdin when reconstituted with cytochrome P450 reductase. Supporting Evidence: PMID:7703255 converts heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:22419571 Endoplasmic reticulum anchored heme-oxygenase 1 faces the cy... | ACCEPT | Summary: Protease-protection assays show endogenous HO-1 is membrane-bound in the ER with its active site facing the cytosol. Core location. Reason: Establishes ER-membrane anchoring and cytosolic-facing topology of HO-1. Supporting Evidence: PMID:22419571 we determined that heme-oxygenase 1 is membrane-bound and faces the cytosol in non-activated macrophages in vivo. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-9708558 | KEEP AS NON CORE | Summary: Reactome models a stress-induced translocation of HO-1 from the ER to the mitochondrial outer membrane. A secondary, context-dependent sub-pool. Reason: Mitochondrial HO-1 has been reported under stress conditions but is not the primary location; retained as non-core. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9708536 | KEEP AS NON CORE | Summary: Reactome models nuclear translocation of HO-1. A stress/context-dependent sub-pool of a cleaved form, not the primary location. Reason: Nuclear HO-1 is a secondary phenomenon tied to proteolytic processing under stress; kept as non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9609921 | KEEP AS NON CORE | Summary: Reactome cytosol location, consistent with tail-anchored protein handling (SGTA/insertion pathway) and the cytosol-facing catalytic domain / soluble cleaved form. Reason: Consistent with the cytosol-facing active site and the soluble form; the primary anchored location remains the ER membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9708457 | KEEP AS NON CORE | Summary: Reactome cytosol location associated with HM13-mediated cleavage of the HMOX1 dimer, generating the soluble form. Reason: Reflects the soluble/cleaved HO-1 form; non-core relative to the ER-membrane-anchored enzyme. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9708536 | KEEP AS NON CORE | Summary: Reactome cytosol location (precursor step to nuclear translocation). Reason: Context-dependent cytosolic pool; non-core relative to the ER-membrane location. |
| GO:0005198 structural molecule activity | IMP PMID:19556236 Oligomerization is crucial for the stability and function of... | MARK AS OVER ANNOTATED | Summary: This annotation mis-types the homo-oligomerization observation of PMID:19556236. HO-1 is an enzyme, not a structural molecule; the correct MF is protein homodimerization activity. Reason: Structural molecule activity implies a scaffolding/structural role; HO-1's oligomerization is better captured by protein homodimerization activity (GO:0042803, separately annotated). The enzyme's function is catalytic, not structural. |
| GO:0042802 identical protein binding | IPI PMID:19556236 Oligomerization is crucial for the stability and function of... | MODIFY | Summary: Captures HO-1 self-association. Better represented by the more informative protein homodimerization activity term. Reason: HO-1 forms homodimers/oligomers via its transmembrane segment; the specific MF protein homodimerization activity (GO:0042803) is more informative than the generic identical protein binding. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:19556236 here we showed that HO-1 forms dimers/oligomers in the ER. |
| GO:0090050 positive regulation of cell migration involved in sprouting angiogenesis | IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | KEEP AS NON CORE | Summary: HO-1 acts in a hypoxia/miR-101-NRF2-HO-1/VEGF/eNOS angiogenic axis promoting angiogenesis. A downstream, context-specific physiological role. Reason: Pro-angiogenic role of HO-1 in specific vascular contexts; downstream of its enzymatic products (CO), not the core molecular function. |
| GO:1903589 positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis | IGI PMID:24844779 Hypoxia-responsive microRNA-101 promotes angiogenesis via he... | KEEP AS NON CORE | Summary: Same miR-101/HO-1/VEGF angiogenic axis; downstream endothelial proliferation phenotype. Reason: Context-specific downstream physiological role of HO-1 in angiogenesis; not core. |
| GO:0045766 positive regulation of angiogenesis | IDA PMID:21788589 MicroRNA-24 regulates vascularity after myocardial infarctio... | KEEP AS NON CORE | Summary: HO-1 is implicated in the pro-angiogenic response after myocardial infarction (miR-24 context). Downstream physiological role. Reason: Pro-angiogenic effect of HO-1 in the cardiovascular context; downstream of the enzymatic function. |
| GO:0005515 protein binding | IPI PMID:21597468 Transformation of eEF1BΞ΄ into heat-shock response transcript... | MARK AS OVER ANNOTATED | Summary: Bare protein binding in the context of eEF1Bdelta (eEF1BdeltaL) binding NRF2 and inducing HO-1. Uninformative for HO-1 molecular function. Reason: The paper concerns eEF1BdeltaL-driven NRF2-dependent HO-1 induction; a bare protein binding annotation on HO-1 does not convey a specific molecular function. |
| GO:0034605 cellular response to heat | IMP PMID:21597468 Transformation of eEF1BΞ΄ into heat-shock response transcript... | KEEP AS NON CORE | Summary: HO-1 (HSP32) is a heat/stress-inducible protein; induction under heat-shock response is consistent, but this is a stress-response consequence. Reason: HO-1 is induced as part of the heat-shock/stress response; a downstream physiological role rather than the core molecular function. |
| GO:0005783 endoplasmic reticulum | IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind... | KEEP AS NON CORE | Summary: ER localization consistent with the anchored enzyme; less specific than ER membrane. Reason: Correct but subsumed by the more specific ER membrane core location. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind... | KEEP AS NON CORE | Summary: Perinuclear (ER-associated) staining reported alongside the STC2 complex study. A plausible ER-adjacent distribution. Reason: Consistent with the perinuclear ER distribution of HO-1; secondary to the ER membrane location. |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | IMP PMID:18202225 HO-1 underlies resistance of AML cells to TNF-induced apopto... | KEEP AS NON CORE | Summary: HO-1 induction underlies resistance of AML cells to TNF-induced apoptosis; supports an anti-apoptotic role in extrinsic death-receptor signaling. Reason: A genuine cytoprotective/anti-apoptotic downstream role of HO-1, not the core molecular function. Supporting Evidence: PMID:18202225 HO-1 was responsible for the resistance of AML cells to the cytotoxic actions of TNF. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-189398 | ACCEPT | Summary: Reactome (heme cleavage reaction) places the HMOX1 dimer in the ER membrane. Core location. Reason: Consistent with the experimentally supported ER membrane location. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6797268 | ACCEPT | Summary: Reactome (HMOX1 expression) ER membrane location. Core location. Reason: Consistent with the ER membrane core location. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9707645 | ACCEPT | Summary: Reactome (HMOX1 dimer formation) ER membrane location. Core location. Reason: Consistent with the ER membrane core location. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9708457 | ACCEPT | Summary: Reactome (HM13 cleavage of HMOX1 dimer) ER membrane location. Core location. Reason: Consistent with the ER membrane core location. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9708558 | ACCEPT | Summary: Reactome (ER-to-mitochondria translocation step) ER membrane starting location. Core. Reason: Consistent with the ER membrane core location. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9759176 | ACCEPT | Summary: Reactome (NFE2L2-dependent HMOX1 expression) ER membrane location. Core. Reason: Consistent with the ER membrane core location. |
| GO:0006879 intracellular iron ion homeostasis | IMP PMID:22989377 Haem oxygenase-1 overexpression alters intracellular iron di... | KEEP AS NON CORE | Summary: HO-1 overexpression alters intracellular iron distribution, rerouting iron into ferritin and reducing redox-active loose iron. Reason: Downstream iron-handling consequence of heme degradation; supports cytoprotection but is not the core molecular function. Supporting Evidence: PMID:22989377 It appears that HO-1 overexpression leads to enhanced destruction of haem, consequent 2-3-fold induction of ferritin |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IDA PMID:17600318 BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent ... | MARK AS OVER ANNOTATED | Summary: HO-1 is a BMP4 target in pulmonary artery smooth muscle. The cited paper actually shows HO-1 inhibits proliferation; the direction here is questionable. Reason: Context-specific smooth-muscle role. Note PMID:17600318 reports HO-1 overexpression inhibits SMC proliferation (growth-inhibitory), so a positive-regulation direction is not well supported by this reference; marked as over-annotated because the cited evidence contradicts the positive-regulation direction. Downstream of the enzymatic function regardless. |
| GO:0048662 negative regulation of smooth muscle cell proliferation | IDA PMID:17600318 BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent ... | KEEP AS NON CORE | Summary: Consistent with the cited paper: HO-1 overexpression inhibits smooth muscle cell proliferation. Reason: Downstream anti-proliferative role of HO-1 in vascular smooth muscle; supported by the reference, but not the core molecular function. Supporting Evidence: PMID:17600318 overexpression of HO-1 in PASMCs inhibited serum-stimulated [3H]-thymidine incorporation. |
| GO:0004392 heme oxygenase (decyclizing) activity | IMP PMID:19556236 Oligomerization is crucial for the stability and function of... | ACCEPT | Summary: Mutagenesis affecting oligomerization reduces microsomal HO activity, supporting the catalytic function. Core. Reason: The W270N mutation reduced HO enzymatic activity, confirming HO-1 catalytic activity in the ER. Supporting Evidence: PMID:19556236 the microsomal HO activity of the W270N mutant was significantly lower than that of the wild type. |
| GO:0005783 endoplasmic reticulum | IDA PMID:19556236 Oligomerization is crucial for the stability and function of... | KEEP AS NON CORE | Summary: ER localization directly observed; less specific than ER membrane. Reason: Correct but subsumed by the more specific ER membrane core location. |
| GO:0042803 protein homodimerization activity | IDA PMID:19556236 Oligomerization is crucial for the stability and function of... | KEEP AS NON CORE | Summary: HO-1 forms homodimers/oligomers in the ER via its transmembrane segment; this is directly demonstrated and required for stability/function. Reason: A real, functionally important molecular property, but supportive of (not equivalent to) the core catalytic function; retained as non-core. Supporting Evidence: PMID:19556236 here we showed that HO-1 forms dimers/oligomers in the ER. |
| GO:0001525 angiogenesis | TAS PMID:12239590 Significance of heme oxygenase in prolactin-mediated cell pr... | KEEP AS NON CORE | Summary: HO-1 contributes to prolactin-mediated endothelial proliferation and angiogenesis. A downstream vascular role. Reason: Pleiotropic angiogenic role of HO-1; downstream of enzymatic products, not core. |
| GO:0001935 endothelial cell proliferation | TAS PMID:12239590 Significance of heme oxygenase in prolactin-mediated cell pr... | KEEP AS NON CORE | Summary: HO-1 promotes endothelial cell proliferation in the prolactin/angiogenesis context. Downstream role. Reason: Context-specific downstream proliferative role; not core. |
| GO:0002246 wound healing involved in inflammatory response | IMP PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | KEEP AS NON CORE | Summary: Human HO-1 deficiency is associated with impaired healing/tissue protection under inflammatory stress. A downstream physiological role. Reason: Organism-level consequence of losing HO-1 cytoprotection; downstream of the enzymatic function. |
| GO:0002686 negative regulation of leukocyte migration | TAS PMID:14525760 Bifunctional role for VEGF-induced heme oxygenase-1 in vivo:... | KEEP AS NON CORE | Summary: HO-1 inhibits leukocytic infiltration (anti-inflammatory) in the VEGF-induced context. Downstream role. Reason: Anti-inflammatory downstream effect of HO-1; not the core molecular function. |
| GO:0004392 heme oxygenase (decyclizing) activity | IDA PMID:17915953 Expression and characterization of full-length human heme ox... | ACCEPT | Summary: Full-length human HO-1 directly degrades heme, releasing iron and CO. Core molecular function. Reason: Purified full-length hHO-1 degrades heme at rates comparable to the WT enzyme. Supporting Evidence: PMID:17915953 Heme oxygenase-1 (HO-1) is the chief regulatory enzyme in the oxidative degradation of heme to biliverdin. |
| GO:0005576 extracellular region | TAS PMID:18307065 Decidual expression and maternal serum levels of heme oxygen... | KEEP AS NON CORE | Summary: Elevated HO-1 in maternal serum/decidua in pre-eclampsia; extracellular HO-1 is atypical for an intracellular ER enzyme. Reason: HO-1 is an intracellular ER-membrane enzyme; extracellular detection is a context-specific phenomenon (secretion/release), not a primary functional location. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear localization transferred by similarity from rat (P06762). Reflects a stress-induced cleaved-fragment sub-pool. Reason: Nuclear HO-1 is a secondary, context-dependent phenomenon; not the primary location. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ER localization by similarity; correct but less specific than ER membrane. Reason: Subsumed by the more specific ER membrane core location. |
| GO:0006788 heme oxidation | IDA PMID:17915953 Expression and characterization of full-length human heme ox... | ACCEPT | Summary: HO-1 oxidatively degrades heme; heme oxidation is a correct direct process term. Core. Reason: Reflects the oxidative chemistry of heme degradation directly demonstrated for human HO-1. Supporting Evidence: PMID:17915953 Heme oxygenase-1 (HO-1) is the chief regulatory enzyme in the oxidative degradation of heme to biliverdin. |
| GO:0006979 response to oxidative stress | IMP PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | KEEP AS NON CORE | Summary: Cells from the HO-1-deficient patient are hypersensitive to oxidative/hemin-induced injury, showing HO-1 protects against oxidative stress. Reason: A well-established downstream cytoprotective consequence of HO-1 activity, not the core molecular function. Supporting Evidence: PMID:9884342 An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. |
| GO:0014806 smooth muscle hyperplasia | TAS PMID:18289072 The role of heme oxygenase-1 in T cell-mediated immunity: th... | KEEP AS NON CORE | Summary: HO-1 role in smooth-muscle/immune contexts from a review. A context-specific downstream physiological process. Reason: Pleiotropic downstream role; not the core molecular function. |
| GO:0019899 enzyme binding | ISS PMID:15516695 Involvement of NADPH in the interaction between heme oxygena... | KEEP AS NON CORE | Summary: Reflects HO-1 functionally docking with NADPH-cytochrome P450 reductase (electron donor). Generic term for a real, functionally central interaction. Reason: HO-1 partners with NADPH-CPR to receive catalytic electrons (PMID:15516695). The generic enzyme binding term is uninformative on its own; the functionally specific interaction is part of the catalytic mechanism. Retained as non-core. |
| GO:0020037 heme binding | IDA PMID:17915953 Expression and characterization of full-length human heme ox... | ACCEPT | Summary: Direct heme binding by full-length human HO-1. Core molecular function. Reason: Heme is the substrate/cofactor; binding is required for catalysis and directly characterized. Supporting Evidence: PMID:17915953 the C-terminal 23 amino acids are essential for maximal catalytic activity. |
| GO:0032722 positive regulation of chemokine production | TAS PMID:17652371 Heme oxygenase-1 modulates the expression of the anti-angiog... | KEEP AS NON CORE | Summary: HO-1 modulates the anti-angiogenic chemokine CXCL10 in renal tubular epithelial cells. Context-specific downstream role. Reason: Downstream immunomodulatory effect; not the core molecular function. |
| GO:0034101 erythrocyte homeostasis | IMP PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | KEEP AS NON CORE | Summary: Human HO-1 deficiency causes hemolytic anemia with erythrocyte fragmentation, supporting a role in erythrocyte homeostasis. Reason: Organism-level physiological consequence of losing heme catabolism; downstream of the enzymatic function. Supporting Evidence: PMID:9884342 He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis |
| GO:0034383 low-density lipoprotein particle clearance | TAS PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | KEEP AS NON CORE | Summary: LDL clearance role attributed to HO-1 in the deficiency context. Context-specific downstream physiological role. Reason: Downstream/indirect physiological role; not the core molecular function. |
| GO:0035094 response to nicotine | IDA PMID:18205746 Differential induction of heme oxygenase-1 against nicotine-... | KEEP AS NON CORE | Summary: HO-1 is induced by nicotine and plays a cytoprotective role against nicotine-induced cytotoxicity in oral keratinocytes. Reason: A stress-response/cytoprotective consequence of HO-1 induction; not the core molecular function. Supporting Evidence: PMID:18205746 HO-1 plays a principal role in the protective response to nicotine |
| GO:0035556 intracellular signal transduction | TAS PMID:17652371 Heme oxygenase-1 modulates the expression of the anti-angiog... | KEEP AS NON CORE | Summary: Broad signaling role attributed to HO-1 (via CO/products). Very general downstream term. Reason: HO-1 products (notably CO) act as signaling molecules, but this generic term is a downstream consequence, not the core function. |
| GO:0042167 heme catabolic process | IDA PMID:17915953 Expression and characterization of full-length human heme ox... | ACCEPT | Summary: Direct demonstration of heme degradation by human HO-1. Core biological process. Reason: Full-length human HO-1 degrades heme to biliverdin, releasing iron and CO. Supporting Evidence: PMID:17915953 In the process of heme degradation, HO-1 receives the electrons necessary for catalysis from the flavoprotein NADPH cytochrome P450 reductase (CPR), releasing free iron and carbon monoxide. |
| GO:0042542 response to hydrogen peroxide | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: HO-1 is induced by and protects against hydrogen peroxide/oxidative stress (transferred by similarity from rat). Downstream stress-response role. Reason: A genuine downstream oxidative-stress-response role; not the core molecular function. |
| GO:0045765 regulation of angiogenesis | TAS PMID:17652371 Heme oxygenase-1 modulates the expression of the anti-angiog... | KEEP AS NON CORE | Summary: HO-1 modulates angiogenesis via CXCL10/chemokine effects. Context-specific downstream role. Reason: Pleiotropic angiogenic regulatory role; downstream of enzymatic products, not core. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | HMP PMID:12761501 Large-scale identification and characterization of human gen... | MARK AS OVER ANNOTATED | Summary: HMOX1 cDNA scored as an NF-kappaB pathway activator in a large-scale overexpression luciferase screen. High-throughput, overexpression-based inference. Reason: Derived from a genome-scale overexpression reporter screen (HMP); HO-1 is generally anti-inflammatory in physiological settings, so a positive-regulation-of-NF-kappaB role is not well supported biologically. Retained but flagged as an over-annotation. |
| GO:0004392 heme oxygenase (decyclizing) activity | TAS PMID:9884342 Oxidative stress causes enhanced endothelial cell injury in ... | ACCEPT | Summary: Author statement of HO-1's heme oxygenase activity in the deficiency case report. Core molecular function. Reason: Consistent with the directly demonstrated core catalytic function. |
| GO:0005783 endoplasmic reticulum | TAS PMID:3345742 Human heme oxygenase cDNA and induction of its mRNA by hemin... | KEEP AS NON CORE | Summary: Early author statement of ER localization; correct but less specific than ER membrane. Reason: Subsumed by the more specific ER membrane core location. |
| GO:0016020 membrane | TAS PMID:3345742 Human heme oxygenase cDNA and induction of its mRNA by hemin... | MARK AS OVER ANNOTATED | Summary: Generic membrane location. Uninformative given the specific ER membrane annotations. Reason: The unspecific parent term membrane adds no information beyond the well-supported ER membrane (GO:0005789) location. |
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