id: P09601
gene_symbol: HMOX1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function of HMOX1, supported phylogenetically and by direct human
      biochemistry. This is the rate-limiting activity of heme catabolism.
    action: ACCEPT
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less specific than endoplasmic reticulum membrane (GO:0005789), which is the
      experimentally supported core location. Retained as non-core.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      HO-1 is a canonical oxidative-stress-response enzyme; its induction and products protect
      cells from oxidative injury.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Heme is the substrate/cofactor of HO-1; heme binding is a core, experimentally validated
      molecular function.
    action: ACCEPT
    reason: >-
      Heme-binding residues are crystallographically resolved (PubMed:12842469) and binding is
      directly characterized (PMID:17915953). Required for catalysis.
- term:
    id: GO:0042167
    label: heme catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process: HMOX1 catalyzes the rate-limiting step of heme catabolism.
    action: ACCEPT
    reason: >-
      Directly supported by human biochemistry (PMID:7703255, PMID:17915953) and appropriately
      propagated by IBA.
- term:
    id: GO:0006788
    label: heme oxidation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      HO-1 oxidatively cleaves the heme ring; heme oxidation is a correct direct process term.
    action: ACCEPT
    reason: >-
      Represents the oxidative chemistry of the core catalytic activity; also IDA in
      PMID:17915953.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core catalytic activity via InterPro/EC/Rhea; correct.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally validated core function and the EC 1.14.14.18 /
      RHEA:21764 catalytic reaction in UniProt.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Correct core location, derived from the UniProt Subcellular Location vocabulary mapping.
    action: ACCEPT
    reason: >-
      HMOX1 is a tail-anchored ER membrane protein; multiple experimental annotations agree
      (PubMed:19556236, 22419571, 27184847).
- term:
    id: GO:0006788
    label: heme oxidation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO assignment of heme oxidation from the heme oxygenase domain; correct.
    action: ACCEPT
    reason: >-
      Matches the core catalytic chemistry and the InterPro heme oxygenase signatures.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a high-throughput YFP-complementation telomere-signaling screen
      (interaction with POT1). Uninformative for HO-1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from the HuRI reference binary interactome (many ER/membrane
      partners). Uninformative for HO-1 function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32353859
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a SARS-CoV-2 host-interactome map (ORF3a). Non-specific.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32838362
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a virus-host interactome/proteomic survey (ORF3a). Non-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput host-virus interaction mapping; uninformative bare protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33060197
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a comparative coronavirus host-interactome network (ORF3a).
      Non-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput host-virus interactome; uninformative bare protein binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36217030
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a comprehensive SARS-CoV-2-human interactome (ORF3a).
      Non-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput host-virus interactome; uninformative bare protein binding.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer of the core catalytic activity from mouse Hmox1; correct.
    action: ACCEPT
    reason: >-
      Redundant with the directly demonstrated human activity; consistent and correct.
- term:
    id: GO:1900016
    label: negative regulation of cytokine production involved in inflammatory response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Anti-inflammatory role transferred by similarity from mouse Hmox1. Consistent with HO-1
      being anti-inflammatory, but a downstream physiological consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine downstream effect of HO-1 products (CO, bilirubin) on inflammation, but not the
      core molecular function; ISS-based.
- term:
    id: GO:0110076
    label: negative regulation of ferroptosis
  evidence_type: IMP
  original_reference_id: PMID:26403645
  qualifier: involved_in
  review:
    summary: >-
      Knockdown of HO-1 (with NQO1 and FTH1), an NRF2 target, promoted ferroptosis in HCC cells,
      supporting a protective role.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:26403645
      supporting_text: >-
        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.
- term:
    id: GO:0042167
    label: heme catabolic process
  evidence_type: IDA
  original_reference_id: PMID:7703255
  qualifier: involved_in
  review:
    summary: >-
      Direct demonstration that human HO-1 converts heme to biliverdin, defining its role in
      heme catabolism. Core process.
    action: ACCEPT
    reason: >-
      Truncated hHO-1 reconstituted with cytochrome P450 reductase converts heme to biliverdin.
    supported_by:
    - reference_id: PMID:7703255
      supporting_text: >-
        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.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      HO-1 is an enzyme, not a transcription factor. This ISS (transferred from rat P06762)
      likely over-interprets nuclear-translocation observations.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IMP
  original_reference_id: PMID:19556236
  qualifier: located_in
  review:
    summary: >-
      Experimental support that HO-1 resides and functions in the ER membrane, with
      oligomerization via its transmembrane segment. Core location.
    action: ACCEPT
    reason: >-
      HO-1 is anchored in the ER by a single C-terminal transmembrane segment; oligomerization
      is required for stability/function there.
    supported_by:
    - reference_id: PMID:19556236
      supporting_text: >-
        a stress-inducible enzyme anchored in the endoplasmic
        reticulum (ER) by a single transmembrane segment (TMS) located at the C
        terminus
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:27184847
  qualifier: located_in
  review:
    summary: >-
      APEX proximity fingerprinting confirmed the ER membrane localization and membrane topology
      of HMOX1. Core location.
    action: ACCEPT
    reason: >-
      Directly determined membrane protein topology of HMOX1 by APEX labeling.
    supported_by:
    - reference_id: PMID:27184847
      supporting_text: >-
        successfully elucidated the membrane protein topology of HMOX1
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IDA
  original_reference_id: PMID:17915953
  qualifier: involved_in
  review:
    summary: >-
      HO-1 releases free iron during heme degradation, contributing to cellular iron handling.
    action: KEEP_AS_NON_CORE
    reason: >-
      A downstream consequence of the heme oxygenase reaction (release of Fe2+ and rerouting to
      ferritin), not the core molecular function.
    supported_by:
    - reference_id: PMID:17915953
      supporting_text: >-
        HO-1 receives the electrons necessary for catalysis from the
        flavoprotein NADPH cytochrome P450 reductase (CPR), releasing free iron and carbon
        monoxide.
- term:
    id: GO:0060586
    label: multicellular organismal-level iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:9884342
  qualifier: involved_in
  review:
    summary: >-
      Human HO-1 deficiency causes systemic iron deposition and dysregulated iron handling,
      supporting a role in organism-level iron homeostasis.
    action: KEEP_AS_NON_CORE
    reason: >-
      An organism-level physiological consequence of losing heme catabolism, downstream of the
      core enzymatic function.
    supported_by:
    - reference_id: PMID:9884342
      supporting_text: >-
        Iron deposition was noted in renal and hepatic tissue.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35239449
  qualifier: enables
  review:
    summary: >-
      Bare protein binding capturing the HMOX1-SARS-CoV-2 ORF3a interaction. The interaction is
      real but the term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: ISS
  original_reference_id: PMID:11447290
  qualifier: involved_in
  review:
    summary: >-
      Anti-inflammatory role transferred by similarity from rat Hmox1 (protection against
      hypoxic pulmonary inflammation).
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine downstream anti-inflammatory effect of HO-1 activity/products, not the core
      molecular function; ISS-based.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IMP
  original_reference_id: PMID:11121422
  qualifier: enables
  review:
    summary: >-
      Mutagenesis of active-site Asp-140 abolishes heme oxygenase activity, directly confirming
      the catalytic function. Core.
    action: ACCEPT
    reason: >-
      D140A/F/L/H/N mutants lose heme oxygenase (biliverdin-forming) activity, establishing the
      catalytic role of the residue and the enzyme.
    supported_by:
    - reference_id: PMID:11121422
      supporting_text: >-
        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.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IDA
  original_reference_id: PMID:7703255
  qualifier: enables
  review:
    summary: >-
      Direct biochemical demonstration of human heme oxygenase activity (heme to biliverdin).
      Core molecular function.
    action: ACCEPT
    reason: >-
      Purified human HO-1 converts heme to biliverdin when reconstituted with cytochrome P450
      reductase.
    supported_by:
    - reference_id: PMID:7703255
      supporting_text: >-
        converts
        heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:22419571
  qualifier: located_in
  review:
    summary: >-
      Protease-protection assays show endogenous HO-1 is membrane-bound in the ER with its
      active site facing the cytosol. Core location.
    action: ACCEPT
    reason: >-
      Establishes ER-membrane anchoring and cytosolic-facing topology of HO-1.
    supported_by:
    - reference_id: PMID:22419571
      supporting_text: >-
        we
        determined that heme-oxygenase 1 is membrane-bound and faces the cytosol in non-activated
        macrophages in vivo.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708558
  qualifier: located_in
  review:
    summary: >-
      Reactome models a stress-induced translocation of HO-1 from the ER to the mitochondrial
      outer membrane. A secondary, context-dependent sub-pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial HO-1 has been reported under stress conditions but is not the primary
      location; retained as non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708536
  qualifier: located_in
  review:
    summary: >-
      Reactome models nuclear translocation of HO-1. A stress/context-dependent sub-pool of a
      cleaved form, not the primary location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear HO-1 is a secondary phenomenon tied to proteolytic processing under stress; kept
      as non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9609921
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol location, consistent with tail-anchored protein handling (SGTA/insertion
      pathway) and the cytosol-facing catalytic domain / soluble cleaved form.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the cytosol-facing active site and the soluble form; the primary anchored
      location remains the ER membrane.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708457
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol location associated with HM13-mediated cleavage of the HMOX1 dimer,
      generating the soluble form.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the soluble/cleaved HO-1 form; non-core relative to the ER-membrane-anchored
      enzyme.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708536
  qualifier: located_in
  review:
    summary: >-
      Reactome cytosol location (precursor step to nuclear translocation).
    action: KEEP_AS_NON_CORE
    reason: >-
      Context-dependent cytosolic pool; non-core relative to the ER-membrane location.
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: IMP
  original_reference_id: PMID:19556236
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19556236
  qualifier: enables
  review:
    summary: >-
      Captures HO-1 self-association. Better represented by the more informative protein
      homodimerization activity term.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
    supported_by:
    - reference_id: PMID:19556236
      supporting_text: >-
        here we showed that HO-1 forms
        dimers/oligomers in the ER.
- term:
    id: GO:0090050
    label: positive regulation of cell migration involved in sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:24844779
  qualifier: involved_in
  review:
    summary: >-
      HO-1 acts in a hypoxia/miR-101-NRF2-HO-1/VEGF/eNOS angiogenic axis promoting angiogenesis.
      A downstream, context-specific physiological role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pro-angiogenic role of HO-1 in specific vascular contexts; downstream of its enzymatic
      products (CO), not the core molecular function.
- term:
    id: GO:1903589
    label: positive regulation of blood vessel endothelial cell proliferation involved
      in sprouting angiogenesis
  evidence_type: IGI
  original_reference_id: PMID:24844779
  qualifier: involved_in
  review:
    summary: >-
      Same miR-101/HO-1/VEGF angiogenic axis; downstream endothelial proliferation phenotype.
    action: KEEP_AS_NON_CORE
    reason: >-
      Context-specific downstream physiological role of HO-1 in angiogenesis; not core.
- term:
    id: GO:0045766
    label: positive regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:21788589
  qualifier: involved_in
  review:
    summary: >-
      HO-1 is implicated in the pro-angiogenic response after myocardial infarction (miR-24
      context). Downstream physiological role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pro-angiogenic effect of HO-1 in the cardiovascular context; downstream of the enzymatic
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21597468
  qualifier: enables
  review:
    summary: >-
      Bare protein binding in the context of eEF1Bdelta (eEF1BdeltaL) binding NRF2 and inducing
      HO-1. Uninformative for HO-1 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0034605
    label: cellular response to heat
  evidence_type: IMP
  original_reference_id: PMID:21597468
  qualifier: involved_in
  review:
    summary: >-
      HO-1 (HSP32) is a heat/stress-inducible protein; induction under heat-shock response is
      consistent, but this is a stress-response consequence.
    action: KEEP_AS_NON_CORE
    reason: >-
      HO-1 is induced as part of the heat-shock/stress response; a downstream physiological
      role rather than the core molecular function.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:22503972
  qualifier: located_in
  review:
    summary: >-
      ER localization consistent with the anchored enzyme; less specific than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but subsumed by the more specific ER membrane core location.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22503972
  qualifier: located_in
  review:
    summary: >-
      Perinuclear (ER-associated) staining reported alongside the STC2 complex study. A
      plausible ER-adjacent distribution.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the perinuclear ER distribution of HO-1; secondary to the ER membrane
      location.
- term:
    id: GO:1902042
    label: negative regulation of extrinsic apoptotic signaling pathway via death domain
      receptors
  evidence_type: IMP
  original_reference_id: PMID:18202225
  qualifier: involved_in
  review:
    summary: >-
      HO-1 induction underlies resistance of AML cells to TNF-induced apoptosis; supports an
      anti-apoptotic role in extrinsic death-receptor signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine cytoprotective/anti-apoptotic downstream role of HO-1, not the core molecular
      function.
    supported_by:
    - reference_id: PMID:18202225
      supporting_text: >-
        HO-1 was responsible for the resistance of AML
        cells to the cytotoxic actions of TNF.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-189398
  qualifier: located_in
  review:
    summary: >-
      Reactome (heme cleavage reaction) places the HMOX1 dimer in the ER membrane. Core location.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally supported ER membrane location.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6797268
  qualifier: located_in
  review:
    summary: >-
      Reactome (HMOX1 expression) ER membrane location. Core location.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane core location.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9707645
  qualifier: located_in
  review:
    summary: >-
      Reactome (HMOX1 dimer formation) ER membrane location. Core location.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane core location.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708457
  qualifier: located_in
  review:
    summary: >-
      Reactome (HM13 cleavage of HMOX1 dimer) ER membrane location. Core location.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane core location.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708558
  qualifier: located_in
  review:
    summary: >-
      Reactome (ER-to-mitochondria translocation step) ER membrane starting location. Core.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane core location.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759176
  qualifier: located_in
  review:
    summary: >-
      Reactome (NFE2L2-dependent HMOX1 expression) ER membrane location. Core.
    action: ACCEPT
    reason: >-
      Consistent with the ER membrane core location.
- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:22989377
  qualifier: involved_in
  review:
    summary: >-
      HO-1 overexpression alters intracellular iron distribution, rerouting iron into ferritin
      and reducing redox-active loose iron.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream iron-handling consequence of heme degradation; supports cytoprotection but is
      not the core molecular function.
    supported_by:
    - reference_id: PMID:22989377
      supporting_text: >-
        It appears that HO-1
        overexpression leads to enhanced destruction of haem, consequent 2-3-fold
        induction of ferritin
- term:
    id: GO:0048661
    label: positive regulation of smooth muscle cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:17600318
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0048662
    label: negative regulation of smooth muscle cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:17600318
  qualifier: involved_in
  review:
    summary: >-
      Consistent with the cited paper: HO-1 overexpression inhibits smooth muscle cell
      proliferation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream anti-proliferative role of HO-1 in vascular smooth muscle; supported by the
      reference, but not the core molecular function.
    supported_by:
    - reference_id: PMID:17600318
      supporting_text: >-
        overexpression of HO-1 in PASMCs inhibited serum-stimulated [3H]-thymidine
        incorporation.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IMP
  original_reference_id: PMID:19556236
  qualifier: enables
  review:
    summary: >-
      Mutagenesis affecting oligomerization reduces microsomal HO activity, supporting the
      catalytic function. Core.
    action: ACCEPT
    reason: >-
      The W270N mutation reduced HO enzymatic activity, confirming HO-1 catalytic activity in
      the ER.
    supported_by:
    - reference_id: PMID:19556236
      supporting_text: >-
        the microsomal
        HO activity of the W270N mutant was significantly lower than that of the wild
        type.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19556236
  qualifier: located_in
  review:
    summary: >-
      ER localization directly observed; less specific than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but subsumed by the more specific ER membrane core location.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:19556236
  qualifier: enables
  review:
    summary: >-
      HO-1 forms homodimers/oligomers in the ER via its transmembrane segment; this is directly
      demonstrated and required for stability/function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A real, functionally important molecular property, but supportive of (not equivalent to)
      the core catalytic function; retained as non-core.
    supported_by:
    - reference_id: PMID:19556236
      supporting_text: >-
        here we showed that HO-1 forms
        dimers/oligomers in the ER.
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: TAS
  original_reference_id: PMID:12239590
  qualifier: involved_in
  review:
    summary: >-
      HO-1 contributes to prolactin-mediated endothelial proliferation and angiogenesis. A
      downstream vascular role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pleiotropic angiogenic role of HO-1; downstream of enzymatic products, not core.
- term:
    id: GO:0001935
    label: endothelial cell proliferation
  evidence_type: TAS
  original_reference_id: PMID:12239590
  qualifier: involved_in
  review:
    summary: >-
      HO-1 promotes endothelial cell proliferation in the prolactin/angiogenesis context.
      Downstream role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Context-specific downstream proliferative role; not core.
- term:
    id: GO:0002246
    label: wound healing involved in inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:9884342
  qualifier: involved_in
  review:
    summary: >-
      Human HO-1 deficiency is associated with impaired healing/tissue protection under
      inflammatory stress. A downstream physiological role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Organism-level consequence of losing HO-1 cytoprotection; downstream of the enzymatic
      function.
- term:
    id: GO:0002686
    label: negative regulation of leukocyte migration
  evidence_type: TAS
  original_reference_id: PMID:14525760
  qualifier: involved_in
  review:
    summary: >-
      HO-1 inhibits leukocytic infiltration (anti-inflammatory) in the VEGF-induced context.
      Downstream role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Anti-inflammatory downstream effect of HO-1; not the core molecular function.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: IDA
  original_reference_id: PMID:17915953
  qualifier: enables
  review:
    summary: >-
      Full-length human HO-1 directly degrades heme, releasing iron and CO. Core molecular
      function.
    action: ACCEPT
    reason: >-
      Purified full-length hHO-1 degrades heme at rates comparable to the WT enzyme.
    supported_by:
    - reference_id: PMID:17915953
      supporting_text: >-
        Heme oxygenase-1 (HO-1) is the chief regulatory
        enzyme in the oxidative degradation of heme to biliverdin.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: PMID:18307065
  qualifier: located_in
  review:
    summary: >-
      Elevated HO-1 in maternal serum/decidua in pre-eclampsia; extracellular HO-1 is atypical
      for an intracellular ER enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      HO-1 is an intracellular ER-membrane enzyme; extracellular detection is a context-specific
      phenomenon (secretion/release), not a primary functional location.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization transferred by similarity from rat (P06762). Reflects a stress-induced
      cleaved-fragment sub-pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Nuclear HO-1 is a secondary, context-dependent phenomenon; not the primary location.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ER localization by similarity; correct but less specific than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Subsumed by the more specific ER membrane core location.
- term:
    id: GO:0006788
    label: heme oxidation
  evidence_type: IDA
  original_reference_id: PMID:17915953
  qualifier: involved_in
  review:
    summary: >-
      HO-1 oxidatively degrades heme; heme oxidation is a correct direct process term. Core.
    action: ACCEPT
    reason: >-
      Reflects the oxidative chemistry of heme degradation directly demonstrated for human HO-1.
    supported_by:
    - reference_id: PMID:17915953
      supporting_text: >-
        Heme oxygenase-1 (HO-1) is the chief regulatory
        enzyme in the oxidative degradation of heme to biliverdin.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:9884342
  qualifier: involved_in
  review:
    summary: >-
      Cells from the HO-1-deficient patient are hypersensitive to oxidative/hemin-induced
      injury, showing HO-1 protects against oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: >-
      A well-established downstream cytoprotective consequence of HO-1 activity, not the core
      molecular function.
    supported_by:
    - reference_id: PMID:9884342
      supporting_text: >-
        An
        LCL derived from the patient was extremely sensitive to hemin-induced cell
        injury.
- term:
    id: GO:0014806
    label: smooth muscle hyperplasia
  evidence_type: TAS
  original_reference_id: PMID:18289072
  qualifier: involved_in
  review:
    summary: >-
      HO-1 role in smooth-muscle/immune contexts from a review. A context-specific downstream
      physiological process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pleiotropic downstream role; not the core molecular function.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: ISS
  original_reference_id: PMID:15516695
  qualifier: enables
  review:
    summary: >-
      Reflects HO-1 functionally docking with NADPH-cytochrome P450 reductase (electron donor).
      Generic term for a real, functionally central interaction.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:17915953
  qualifier: enables
  review:
    summary: >-
      Direct heme binding by full-length human HO-1. Core molecular function.
    action: ACCEPT
    reason: >-
      Heme is the substrate/cofactor; binding is required for catalysis and directly
      characterized.
    supported_by:
    - reference_id: PMID:17915953
      supporting_text: >-
        the C-terminal 23 amino acids are essential for
        maximal catalytic activity.
- term:
    id: GO:0032722
    label: positive regulation of chemokine production
  evidence_type: TAS
  original_reference_id: PMID:17652371
  qualifier: involved_in
  review:
    summary: >-
      HO-1 modulates the anti-angiogenic chemokine CXCL10 in renal tubular epithelial cells.
      Context-specific downstream role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream immunomodulatory effect; not the core molecular function.
- term:
    id: GO:0034101
    label: erythrocyte homeostasis
  evidence_type: IMP
  original_reference_id: PMID:9884342
  qualifier: involved_in
  review:
    summary: >-
      Human HO-1 deficiency causes hemolytic anemia with erythrocyte fragmentation, supporting a
      role in erythrocyte homeostasis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Organism-level physiological consequence of losing heme catabolism; downstream of the
      enzymatic function.
    supported_by:
    - reference_id: PMID:9884342
      supporting_text: >-
        He has been suffering from persistent hemolytic anemia characterized by marked
        erythrocyte fragmentation and intravascular hemolysis
- term:
    id: GO:0034383
    label: low-density lipoprotein particle clearance
  evidence_type: TAS
  original_reference_id: PMID:9884342
  qualifier: involved_in
  review:
    summary: >-
      LDL clearance role attributed to HO-1 in the deficiency context. Context-specific
      downstream physiological role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream/indirect physiological role; not the core molecular function.
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IDA
  original_reference_id: PMID:18205746
  qualifier: involved_in
  review:
    summary: >-
      HO-1 is induced by nicotine and plays a cytoprotective role against nicotine-induced
      cytotoxicity in oral keratinocytes.
    action: KEEP_AS_NON_CORE
    reason: >-
      A stress-response/cytoprotective consequence of HO-1 induction; not the core molecular
      function.
    supported_by:
    - reference_id: PMID:18205746
      supporting_text: >-
        HO-1 plays a principal
        role in the protective response to nicotine
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: TAS
  original_reference_id: PMID:17652371
  qualifier: involved_in
  review:
    summary: >-
      Broad signaling role attributed to HO-1 (via CO/products). Very general downstream term.
    action: KEEP_AS_NON_CORE
    reason: >-
      HO-1 products (notably CO) act as signaling molecules, but this generic term is a
      downstream consequence, not the core function.
- term:
    id: GO:0042167
    label: heme catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17915953
  qualifier: involved_in
  review:
    summary: >-
      Direct demonstration of heme degradation by human HO-1. Core biological process.
    action: ACCEPT
    reason: >-
      Full-length human HO-1 degrades heme to biliverdin, releasing iron and CO.
    supported_by:
    - reference_id: PMID:17915953
      supporting_text: >-
        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.
- term:
    id: GO:0042542
    label: response to hydrogen peroxide
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      HO-1 is induced by and protects against hydrogen peroxide/oxidative stress (transferred by
      similarity from rat). Downstream stress-response role.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine downstream oxidative-stress-response role; not the core molecular function.
- term:
    id: GO:0045765
    label: regulation of angiogenesis
  evidence_type: TAS
  original_reference_id: PMID:17652371
  qualifier: involved_in
  review:
    summary: >-
      HO-1 modulates angiogenesis via CXCL10/chemokine effects. Context-specific downstream role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pleiotropic angiogenic regulatory role; downstream of enzymatic products, not core.
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: HMP
  original_reference_id: PMID:12761501
  qualifier: involved_in
  review:
    summary: >-
      HMOX1 cDNA scored as an NF-kappaB pathway activator in a large-scale overexpression
      luciferase screen. High-throughput, overexpression-based inference.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  evidence_type: TAS
  original_reference_id: PMID:9884342
  qualifier: enables
  review:
    summary: >-
      Author statement of HO-1's heme oxygenase activity in the deficiency case report. Core
      molecular function.
    action: ACCEPT
    reason: >-
      Consistent with the directly demonstrated core catalytic function.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:3345742
  qualifier: located_in
  review:
    summary: >-
      Early author statement of ER localization; correct but less specific than ER membrane.
    action: KEEP_AS_NON_CORE
    reason: >-
      Subsumed by the more specific ER membrane core location.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:3345742
  qualifier: located_in
  review:
    summary: >-
      Generic membrane location. Uninformative given the specific ER membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The unspecific parent term membrane adds no information beyond the well-supported ER
      membrane (GO:0005789) location.
core_functions:
- description: >-
    Heme oxygenase (decyclizing) activity: HMOX1 catalyzes the rate-limiting, oxygen-dependent
    oxidative cleavage of the alpha-methene bridge of heme b, using electrons from
    NADPH--cytochrome P450 reductase, to produce biliverdin IX-alpha, carbon monoxide, and free
    ferrous iron. This is the committed step of heme catabolism.
  molecular_function:
    id: GO:0004392
    label: heme oxygenase (decyclizing) activity
  supported_by:
  - reference_id: PMID:7703255
    supporting_text: >-
      converts
      heme to biliverdin when reconstituted with rat liver cytochrome P450 reductase.
  - reference_id: PMID:11121422
    supporting_text: >-
      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.
  directly_involved_in:
  - id: GO:0042167
    label: heme catabolic process
  - id: GO:0006788
    label: heme oxidation
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: >-
    Heme binding: HMOX1 binds heme b as its substrate/cofactor via active-site residues
    (including the axial His25 iron ligand and Asp140), positioning the porphyrin for
    regiospecific oxidative cleavage.
  molecular_function:
    id: GO:0020037
    label: heme binding
  supported_by:
  - reference_id: PMID:17915953
    supporting_text: >-
      Heme oxygenase-1 (HO-1) is the chief regulatory
      enzyme in the oxidative degradation of heme to biliverdin.
  - reference_id: file:human/HMOX1/HMOX1-uniprot.txt
    supporting_text: >-
      axial binding residue
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: >-
    Protein homodimerization activity: HMOX1 self-associates into homodimers/higher-order
    oligomers through its C-terminal transmembrane segment; this oligomerization is required for
    protein stability and catalytic function in the endoplasmic reticulum membrane.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  supported_by:
  - reference_id: PMID:19556236
    supporting_text: >-
      here we showed that HO-1 forms
      dimers/oligomers in the ER.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11121422
  title: Disruption of an active site hydrogen bond converts human heme oxygenase-1
    into a peroxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Active-site Asp-140 mutagenesis abolishes heme oxygenase (biliverdin-forming) activity of
      human HO-1, directly supporting the core catalytic function.
- id: PMID:11447290
  title: Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory
    and vascular responses to hypoxia.
  findings: []
- id: PMID:12239590
  title: Significance of heme oxygenase in prolactin-mediated cell proliferation and
    angiogenesis in human endothelial cells.
  findings: []
- id: PMID:12761501
  title: Large-scale identification and characterization of human genes that activate
    NF-kappaB and MAPK signaling pathways.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Genome-scale overexpression luciferase screen; supports an NF-kappaB-activating signal from
      HMOX1 cDNA only in that artificial context, hence the over-annotation flag.
- id: PMID:14525760
  title: 'Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of
    angiogenesis and inhibition of leukocytic infiltration.'
  findings: []
- id: PMID:15516695
  title: Involvement of NADPH in the interaction between heme oxygenase-1 and cytochrome
    P450 reductase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Characterizes the functional HO-1/NADPH-CPR interaction (electron donor for catalysis);
      supports the enzyme binding annotation.
- id: PMID:17600318
  title: BMP4 induces HO-1 via a Smad-independent, p38MAPK-dependent pathway in pulmonary
    artery myocytes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows BMP4-induced HO-1 inhibits pulmonary artery SMC proliferation; supports the
      negative-regulation-of-SMC-proliferation annotation but not the positive-regulation one.
- id: PMID:17652371
  title: Heme oxygenase-1 modulates the expression of the anti-angiogenic chemokine
    CXCL-10 in renal tubular epithelial cells.
  findings: []
- id: PMID:17915953
  title: 'Expression and characterization of full-length human heme oxygenase-1: the
    presence of intact membrane-binding region leads to increased binding affinity
    for NADPH cytochrome P450 reductase.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct biochemical characterization of full-length human HO-1 heme degradation and CPR
      binding; supports the core catalytic function and heme binding.
- id: PMID:18202225
  title: HO-1 underlies resistance of AML cells to TNF-induced apoptosis.
  findings: []
- id: PMID:18205746
  title: Differential induction of heme oxygenase-1 against nicotine-induced cytotoxicity
    via the PI3K, MAPK, and NF-kappa B pathways in immortalized and malignant human
    oral keratinocytes.
  findings: []
- id: PMID:18289072
  title: 'The role of heme oxygenase-1 in T cell-mediated immunity: the all encompassing
    enzyme.'
  findings: []
- id: PMID:18307065
  title: Decidual expression and maternal serum levels of heme oxygenase 1 are increased
    in pre-eclampsia.
  findings: []
- id: PMID:19556236
  title: Oligomerization is crucial for the stability and function of heme oxygenase-1
    in the endoplasmic reticulum.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes ER-membrane anchoring, TM-driven homo-oligomerization, and its requirement for
      HO-1 stability and enzymatic activity.
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators
    for telomere signaling in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput YFP-complementation telomere-signaling screen; the HO-1/POT1 hit is a
      generic protein-binding observation without a defined HO-1 function.
- id: PMID:21597468
  title: Transformation of eEF1Bδ into heat-shock response transcription factor by
    alternative splicing.
  findings: []
- id: PMID:21788589
  title: MicroRNA-24 regulates vascularity after myocardial infarction.
  findings: []
- id: PMID:22419571
  title: Endoplasmic reticulum anchored heme-oxygenase 1 faces the cytosol.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Protease-protection assays place endogenous HO-1 in the ER membrane with a cytosol-facing
      active site; supports the core location and topology.
- id: PMID:22503972
  title: Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is
    a heat shock protein.
  findings: []
- id: PMID:22989377
  title: Haem oxygenase-1 overexpression alters intracellular iron distribution.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows HO-1 overexpression reroutes iron into ferritin and reduces redox-active loose iron;
      supports the intracellular iron homeostasis annotation.
- id: PMID:24844779
  title: Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular
    endothelial growth factor axis by targeting cullin 3.
  findings: []
- id: PMID:26403645
  title: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in
    hepatocellular carcinoma cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      HO-1 knockdown (with NQO1/FTH1) promoted ferroptosis; supports a protective
      (negative-regulation-of-ferroptosis) role as an NRF2 target.
- id: PMID:27184847
  title: APEX Fingerprinting Reveals the Subcellular Localization of Proteins of Interest.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      APEX proximity fingerprinting directly resolved HMOX1 membrane topology/ER localization.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput binary interactome (HuRI); numerous ER/membrane partners largely reflect
      co-compartmentalization rather than specific HO-1 functions.
- id: PMID:32353859
  title: A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
  findings: []
- id: PMID:32838362
  title: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors
    Influencing SARS-CoV-2 Pathogenesis.
  findings: []
- id: PMID:33060197
  title: Comparative host-coronavirus protein interaction networks reveal pan-viral
    disease mechanisms.
  findings: []
- id: PMID:3345742
  title: Human heme oxygenase cDNA and induction of its mRNA by hemin.
  findings: []
- id: PMID:35239449
  title: SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and triggers
    sequential ER stress and inflammatory responses during SARS-CoV-2 infection.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Reports HMOX1-ORF3a interaction promoting ORF3a-induced autophagy during SARS-CoV-2
      infection; a host-virus interaction, not a core HO-1 function.
- id: PMID:36217030
  title: A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19
    pathobiology and potential host therapeutic targets.
  findings: []
- id: PMID:7703255
  title: Expression and characterization of truncated human heme oxygenase (hHO-1)
    and a fusion protein of hHO-1 with human cytochrome P450 reductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Truncated human HO-1 converts heme to biliverdin with cytochrome P450 reductase; primary
      evidence for the core catalytic function and the soluble form.
- id: PMID:9884342
  title: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1
    deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First human HMOX1-deficiency case; establishes the in vivo consequences (hemolysis,
      erythrocyte fragmentation, iron deposition, oxidative-stress hypersensitivity).
- id: Reactome:R-HSA-189398
  title: HMOX1 dimer, HMOX2 cleave heme
  findings: []
- id: Reactome:R-HSA-6797268
  title: Expression of HMOX1
  findings: []
- id: Reactome:R-HSA-9609921
  title: SGTA binds Tail-anchored protein
  findings: []
- id: Reactome:R-HSA-9707645
  title: HMOX1 gene produces HMOX1 dimer
  findings: []
- id: Reactome:R-HSA-9708457
  title: HM13 cleaves HMOX1 dimer
  findings: []
- id: Reactome:R-HSA-9708536
  title: HMOX1 translocates from the cytosol to the nucleoplasm
  findings: []
- id: Reactome:R-HSA-9708558
  title: HMOX1 dimer translocates from ER membrane to mitochondrial outer membrane
  findings: []
- id: Reactome:R-HSA-9759176
  title: NFE2L2-dependent HMOX1 gene expression
  findings: []