id: Q96HE7
gene_symbol: ERO1A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ERO1A (ERO1-like protein alpha, formerly ERO1L; endoplasmic reticulum oxidoreductin-1 alpha) is an ER membrane-associated, FAD-dependent flavoprotein sulfhydryl oxidase (EC 1.8.3.2) that drives oxidative protein folding in the endoplasmic reticulum. It reoxidizes the protein disulfide isomerase P4HB/PDI, regenerating PDI's active-site disulfide so that PDI can catalyze further rounds of disulfide-bond formation in nascent secretory proteins; the electrons abstracted are passed via bound FAD to molecular oxygen, producing hydrogen peroxide. It is a peripheral membrane protein on the lumenal side of the ER, retained there through its interaction with ERP44, and is also detected in the Golgi lumen and secreted. Its enzymatic activity is tightly regulated by intramolecular regulatory disulfide bonds (involving Cys94/Cys99/Cys104/Cys131) to limit reactive-oxygen-species accumulation, and is further tuned by FAM20C-mediated phosphorylation at Ser145. ERO1A is induced by hypoxia via the HIF pathway and during the unfolded protein response. Through oxidative folding it supports maturation of disulfide-rich secretory cargo such as immunoglobulins, and participates in ER-stress responses, cholera-toxin retrotranslocation, and ER redox homeostasis.
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ERO1A is a peripheral ER membrane protein acting on the lumenal side; this is its primary site of action and is well supported experimentally and by phylogenetic inference across the EROs family.
    action: ACCEPT
    reason: The ER membrane (lumenal side) is the documented site of action for ERO1A, where it reoxidizes PDI; corroborated by direct evidence.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A secreted/extracellular pool of ERO1A has been reported, but this is peripheral to its core ER oxidoreductase function.
    action: KEEP_AS_NON_CORE
    reason: UniProt records a secreted pool, so the localization is not wrong, but it is a minor/secondary location relative to the ER where ERO1A performs its catalytic role.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Golgi apparatus lumen
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: ER localization is correct and the principal compartment for ERO1A.
    action: ACCEPT
    reason: ERO1A is an ER-resident oxidoreductase; this localization is directly supported.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic localization to ER membrane, consistent with the IBA and experimental evidence.
    action: ACCEPT
    reason: Correct compartment; ERO1A is a peripheral ER membrane protein on the lumenal side.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005796
    label: Golgi lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ERO1A is detected in the Golgi lumen, where it is a FAM20C substrate, but this is secondary to its ER function.
    action: KEEP_AS_NON_CORE
    reason: Golgi lumen localization is documented (FAM20C phosphorylation occurs in the Golgi) but peripheral to the core ER oxidoreductase activity.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Golgi apparatus lumen
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: This term asserts a disulfide REDUCTASE activity. ERO1A is mechanistically an OXIDASE that reoxidizes PDI (i.e. forms disulfides and consumes reducing equivalents), not a reductase. The reductase term is an over-annotation, likely an electronic transfer that mislabels the directionality.
    action: MARK_AS_OVER_ANNOTATED
    reason: ERO1A oxidizes PDI and passes electrons to O2 generating H2O2; it does not function as a protein-disulfide reductase. The catalytic direction recorded by UniProt is dithiol oxidation, contradicting a reductase assignment.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation.
- term:
    id: GO:0016971
    label: flavin-dependent sulfhydryl oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: This is the precise core molecular function of ERO1A - a FAD-dependent sulfhydryl oxidase catalyzing dithiol + O2 = disulfide + H2O2 (RHEA:59116). The falcon deep research independently describes the same electron-flow mechanism with O2 as the terminal electron acceptor.
    action: ACCEPT
    reason: Directly matches the catalytic activity and FAD cofactor of ERO1A and is supported experimentally (EXP entries from PMID:11707400, PMID:29858230).
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Reaction=[protein]-dithiol + O2 = [protein]-disulfide + H2O2'
    - reference_id: file:human/ERO1A/ERO1A-deep-research-falcon.md
      supporting_text: ERO1A then re-oxidizes reduced PDI by accepting electrons through its FAD cofactor, with molecular oxygen (O₂) serving as the terminal electron acceptor
- term:
    id: GO:0016972
    label: thiol oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Thiol oxidase activity is the broader parent of ERO1A's flavin-dependent sulfhydryl oxidase activity; correct but less specific.
    action: ACCEPT
    reason: Correctly captures ERO1A's oxidase activity; the IDA-supported version of the same term (PMID:11707400) confirms it.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'EC=1.8.3.2'
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Dendritic localization is inferred only by similarity to the mouse ortholog (Q8R4A1) and is not established for human ERO1A.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a by-similarity transfer from the rodent ortholog for a neuronal context; it is not a core function and is unsupported by direct human evidence.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: In neurons, it localizes to dendrites (By
- term:
    id: GO:0034975
    label: protein folding in endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ERO1A enables oxidative protein folding in the ER; protein folding in the ER is a valid downstream biological process outcome of its oxidase activity.
    action: KEEP_AS_NON_CORE
    reason: Protein folding in the ER is a process consequence of ERO1A's oxidase activity rather than its direct molecular function; appropriate as a non-core process annotation.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum.
- term:
    id: GO:0071949
    label: FAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ERO1A is a flavoprotein that binds FAD as its cofactor; multiple FAD binding residues are defined in the crystal structure.
    action: ACCEPT
    reason: FAD is the documented cofactor with mapped binding sites (PubMed:20834232, PDB 3AHQ/3AHR); FAD binding is integral to the oxidase mechanism.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Name=FAD; Xref=ChEBI:CHEBI:57692'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17170699
  qualifier: enables
  review:
    summary: IntAct interaction with PDIA3/ERp57 (P30101). Bare protein binding is uninformative; it records a real ER-oxidoreductase interaction but is non-core (and note PMID:11707400 found ERO1A does not alter ERp57 redox state).
    action: KEEP_AS_NON_CORE
    reason: Records a genuine physical interaction within the ER oxidoreductase network, but the uninformative protein binding term should not be elevated to core function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Q96HE7; P30101: PDIA3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20802462
  qualifier: enables
  review:
    summary: IntAct interactions with P4HB/PDI (P07237) and PDIA3 (P30101), the physiological substrates ERO1A reoxidizes. The bare protein binding term is uninformative but the underlying P4HB interaction is biologically central; the falcon deep research notes ERO1A binds PDI with the highest affinity among ER thiol isomerases (Kd 1.7 uM), consistent with PDI being its preferred direct substrate.
    action: KEEP_AS_NON_CORE
    reason: The P4HB interaction underlies ERO1A's catalytic substrate relationship, but the generic protein binding term is uninformative and the informative function is captured by the oxidase MF terms.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Q96HE7; P07237: P4HB'
    - reference_id: file:human/ERO1A/ERO1A-deep-research-falcon.md
      supporting_text: ERO1A exhibits strong substrate selectivity for PDI over other ER oxidoreductases. Quantitative binding studies demonstrate that ERO1A binds PDI with highest affinity (Kd = 1.7 μM)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput yeast two-hybrid interactome capturing an ERO1A-APPBP2 (Q92624) interaction; an isolated binary interaction unrelated to ERO1A's oxidase function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a large-scale binary interactome screen; records an interaction but is uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Q96HE7; Q92624: APPBP2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome map capturing an ERO1A-LHX4 (Q969G2) interaction; a single high-throughput interaction with a homeobox transcription factor unrelated to ERO1A's ER function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a reference binary interactome; uninformative and not part of ERO1A's core oxidative-folding function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'Q96HE7; Q969G2: LHX4'
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: ERO1A is an oxidoreductase; this is a correct but very general parent term.
    action: ACCEPT
    reason: Correct high-level molecular function, subsumed by the more specific flavin-dependent sulfhydryl oxidase activity that is the core function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Oxidoreductase involved in disulfide bond formation in the endoplasmic reticulum.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ERO1A is induced during the UPR and participates in ER-stress responses; this is a plausible process annotation transferred from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: ERO1A is part of the ER stress/UPR program but this is a downstream/contextual process rather than its core molecular function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Plays an important role in ER stress-induced, CHOP-dependent apoptosis
- term:
    id: GO:0051209
    label: release of sequestered calcium ion into cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ERO1A promotes ER Ca2+ release by activating IP3R1 during ER-stress apoptosis; this is inferred from the mouse ortholog and is a specialized downstream role. The falcon deep research corroborates that ERO1A modulates ER Ca2+ release via IP3R (and RyR) channels.
    action: KEEP_AS_NON_CORE
    reason: A genuine but context-specific (ER-stress apoptosis) downstream effect inferred by similarity; non-core relative to the oxidase function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: by activating the inositol 1,4,5-trisphosphate receptor IP3R1
    - reference_id: file:human/ERO1A/ERO1A-deep-research-falcon.md
      supporting_text: ERO1A triggers calcium release from the ER to the cytosol and mitochondria by modulating IP3R and RyR calcium channels
- term:
    id: GO:0070059
    label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ERO1A contributes to CHOP-dependent ER-stress apoptosis (via IP3R1); inferred from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: A documented but specialized downstream signaling role; non-core relative to the core oxidase activity.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: ERO1A is hypoxia-inducible via the HIF pathway; participation in the cellular hypoxia response is supported. The falcon deep research corroborates that ERO1A is transcriptionally induced by HIF-1alpha under hypoxia (notably in tumor microenvironments).
    action: KEEP_AS_NON_CORE
    reason: ERO1A is a hypoxia-induced gene, so a hypoxia-response process annotation is reasonable, but this is a regulatory/contextual process rather than its core function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Stimulated by hypoxia; suggesting that it is regulated via the HIF-pathway.
    - reference_id: file:human/ERO1A/ERO1A-deep-research-falcon.md
      supporting_text: ERO1A expression is strongly induced by hypoxia through hypoxia-inducible factor 1α (HIF-1α)
- term:
    id: GO:0016971
    label: flavin-dependent sulfhydryl oxidase activity
  evidence_type: EXP
  original_reference_id: PMID:11707400
  qualifier: enables
  review:
    summary: Experimentally supported FAD-dependent sulfhydryl oxidase activity - ERO1A oxidizes PDI to drive disulfide bond formation in immunoglobulins.
    action: ACCEPT
    reason: Strong experimental evidence (selective oxidation of PDI); this is the core molecular function of ERO1A.
    supported_by:
    - reference_id: PMID:11707400
      supporting_text: both human Ero1-Lalpha and Ero1-Lbeta (hEROs) facilitate disulfide bond formation in immunoglobulin subunits by selectively oxidizing PDI
- term:
    id: GO:0016971
    label: flavin-dependent sulfhydryl oxidase activity
  evidence_type: EXP
  original_reference_id: PMID:29858230
  qualifier: enables
  review:
    summary: Experimentally supported FAD-dependent sulfhydryl oxidase activity; ERO1A activity is tuned by FAM20C phosphorylation and required for immunoglobulin folding.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; phosphomimetic S145E increases enzyme activity and accelerates immunoglobulin folding.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Shows two-fold increase in enzyme activity. Accelerates immunoglobulin folding.
- term:
    id: GO:0016972
    label: thiol oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:11707400
  qualifier: enables
  review:
    summary: Direct-assay thiol oxidase activity (parent of the flavin-dependent sulfhydryl oxidase term); ERO1A oxidizes PDI thiols.
    action: ACCEPT
    reason: IDA evidence for oxidase activity; correct, though the flavin-dependent sulfhydryl oxidase term is the most precise descriptor.
    supported_by:
    - reference_id: PMID:11707400
      supporting_text: Disulfide bond formation is controlled by hEROs, which stand at a crucial point of an electron-flow starting from nascent secretory proteins and passing through PDI.
- term:
    id: GO:0016972
    label: thiol oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:29858230
  qualifier: enables
  review:
    summary: Direct-assay thiol oxidase activity confirmed in the FAM20C-phosphorylation study.
    action: ACCEPT
    reason: IDA-supported oxidase activity; consistent core molecular function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'EC=1.8.3.2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29858230
  qualifier: enables
  review:
    summary: IntAct interaction with ERP44 (Q9BS26), the partner that retains ERO1A in the ER. Bare protein binding is uninformative but the ERP44 interaction is biologically meaningful (ER retention).
    action: KEEP_AS_NON_CORE
    reason: A real, functionally important interaction (ER retention via ERP44), but the generic protein binding term is uninformative and should not be elevated to a core molecular function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Interacts with ERP44; the interaction results in retention of ERO1A in the endoplasmic reticulum
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:29858230
  qualifier: located_in
  review:
    summary: Direct evidence for a secreted/extracellular pool of ERO1A.
    action: KEEP_AS_NON_CORE
    reason: A genuine secondary localization (secreted), peripheral to the ER site of catalytic action.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Secreted
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:29858230
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization, the principal compartment of ERO1A.
    action: ACCEPT
    reason: IDA-supported ER localization, the core compartment for ERO1A's oxidase function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005796
    label: Golgi lumen
  evidence_type: IDA
  original_reference_id: PMID:29858230
  qualifier: located_in
  review:
    summary: Direct evidence for a Golgi-lumen pool where ERO1A is phosphorylated by FAM20C.
    action: KEEP_AS_NON_CORE
    reason: Genuine secondary localization (Golgi) relevant to FAM20C regulation but peripheral to the ER catalytic role.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Golgi apparatus lumen
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:29858230
  qualifier: involved_in
  review:
    summary: ERO1A is required for proper folding of immunoglobulins; protein folding is a valid downstream process outcome of its oxidase activity.
    action: KEEP_AS_NON_CORE
    reason: Protein folding is the biological-process consequence of ERO1A-driven oxidative folding, downstream of its core oxidase molecular function.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Required for the proper folding of immunoglobulins
- term:
    id: GO:0045454
    label: cell redox homeostasis
  evidence_type: IMP
  original_reference_id: PMID:29858230
  qualifier: involved_in
  review:
    summary: ERO1A is a central determinant of ER redox state; its activity is tightly regulated to balance oxidation and limit ROS.
    action: ACCEPT
    reason: ERO1A genuinely sets/balances ER redox homeostasis (regulatory disulfides and FAM20C tuning); a core biological process for this enzyme.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Enzyme activity is tightly regulated to prevent the accumulation of reactive oxygen species in the endoplasmic reticulum.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput membrane proteome detection; ERO1A is a peripheral membrane protein, so a generic membrane localization is consistent but uninformative.
    action: KEEP_AS_NON_CORE
    reason: Generic membrane localization from a proteomic survey; correct but far less specific than ER membrane.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3341296
  qualifier: located_in
  review:
    summary: Reactome places ERO1A in the ER lumen; ERO1A acts on the lumenal side of the ER membrane, so this is consistent with its site of action.
    action: ACCEPT
    reason: ERO1A is a lumenal-side ER protein; ER lumen localization is consistent with its function and curated by Reactome.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Lumenal side
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS-transferred ER-stress-response role from the mouse ortholog; consistent with ERO1A's UPR induction.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IEA ER-stress annotation; a plausible downstream/contextual process, non-core.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Plays an important role in ER stress-induced, CHOP-dependent apoptosis
- term:
    id: GO:0051209
    label: release of sequestered calcium ion into cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS-transferred Ca2+-release role (via IP3R1) from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Specialized downstream effect during ER-stress apoptosis inferred by similarity; non-core.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: by activating the inositol 1,4,5-trisphosphate receptor IP3R1
- term:
    id: GO:0070059
    label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS-transferred ER-stress apoptosis role from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: Documented but specialized downstream signaling role; non-core relative to the oxidase activity.
    supported_by:
    - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
      supporting_text: Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:10671517
  qualifier: located_in
  review:
    summary: Original characterization showing ERO1-L co-localizes with ER markers.
    action: ACCEPT
    reason: TAS from the founding paper directly establishes ER localization.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: the product of the human ERO1-L gene co-localizes with ER markers and displays Endo-H-sensitive glycans
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: TAS
  original_reference_id: PMID:10671517
  qualifier: involved_in
  review:
    summary: ERO1-L is involved in oxidative ER protein folding; protein folding is the downstream process of its oxidase activity.
    action: KEEP_AS_NON_CORE
    reason: A valid process annotation but downstream of the core oxidase molecular function.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: ERO1-L is involved in oxidative ER protein folding in mammalian cells
- term:
    id: GO:0009266
    label: response to temperature stimulus
  evidence_type: TAS
  original_reference_id: PMID:10671517
  qualifier: involved_in
  review:
    summary: This term derives from ERO1-L complementing the temperature/DTT sensitivity of a yeast ero1-1 thermosensitive mutant - a heterologous complementation assay, not evidence that human ERO1A functions in a temperature-stimulus response.
    action: MARK_AS_OVER_ANNOTATED
    reason: The annotation over-interprets a yeast ts-mutant complementation experiment; it does not reflect a genuine temperature-response biological role for human ERO1A.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: ERO1-L is able to complement several phenotypic traits of the yeast thermosensitive mutant ero1-1, including temperature and dithiothreitol sensitivity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:10671517
  qualifier: located_in
  review:
    summary: ERO1-L behaves as a membrane-associated protein in isolated microsomes.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic membrane localization; the specific ER membrane term is preferred.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: ERO1-L behaves as a type II integral membrane protein
- term:
    id: GO:0043231
    label: intracellular membrane-bounded organelle
  evidence_type: TAS
  original_reference_id: PMID:10671517
  qualifier: located_in
  review:
    summary: Very general organelle localization term, subsumed by the specific ER annotations.
    action: KEEP_AS_NON_CORE
    reason: Uninformative high-level localization; correct but superseded by ER/ER membrane terms.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: co-localizes with ER markers
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10671517
  qualifier: located_in
  review:
    summary: Direct evidence (co-localization with ER markers) for ER localization.
    action: ACCEPT
    reason: IDA-supported ER localization from the founding characterization.
    supported_by:
    - reference_id: PMID:10671517
      supporting_text: co-localizes with ER markers
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:11707400
  qualifier: involved_in
  review:
    summary: ERO1A facilitates disulfide-bond formation in immunoglobulin subunits; protein folding is a downstream process of its oxidase activity.
    action: KEEP_AS_NON_CORE
    reason: Valid downstream process annotation supported by direct evidence, but non-core relative to the oxidase molecular function.
    supported_by:
    - reference_id: PMID:11707400
      supporting_text: hEROs) facilitate disulfide bond formation in immunoglobulin subunits by selectively oxidizing PDI
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 Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Gene Ontology annotation based on RHEA mapping of reactions
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10671517
  title: ERO1-L, a human protein that favors disulfide bond formation in the endoplasmic reticulum.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_10671517.md title matches YAML; original characterization of human ERO1-L (ERO1A) as an ER protein favoring disulfide-bond formation, complementing yeast ero1-1. GOA anchors this PMID to ER localization (GO:0005783) and protein folding (GO:0006457), supporting the core function."
  findings:
  - statement: ERO1-L is an ER-localized, glycosylated membrane-associated protein that complements the yeast ero1-1 mutant and is involved in oxidative ER protein folding; activity requires Cys-394/Cys-397.
    reference_section_type: ABSTRACT
- id: PMID:11707400
  title: Manipulation of oxidative protein folding and PDI redox state in mammalian cells.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_11707400.md title matches YAML; demonstrates ERO1A selectively oxidizes PDI to drive disulfide-bond formation. GOA anchors this PMID to GO:0016971/GO:0016972 (flavin-dependent sulfhydryl oxidase / oxidizing PDI, EXP/IDA), the core molecular function."
  findings:
  - statement: Human Ero1-Lalpha and Ero1-Lbeta facilitate disulfide bond formation in immunoglobulin subunits by selectively oxidizing PDI, standing at a crucial point of an electron flow from nascent secretory proteins through PDI; ERp57 redox state is not affected.
    reference_section_type: ABSTRACT
- id: PMID:17170699
  title: ERp57 is essential for efficient folding of glycoproteins sharing common structural domains.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20802462
  title: Disulphide production by Ero1α-PDI relay is rapid and effectively regulated.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:29858230
  title: Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α.
  findings:
  - statement: FAM20C phosphorylates ERO1A at Ser145 in the Golgi, increasing its enzymatic activity; phosphomimetic S145E doubles activity and accelerates immunoglobulin folding; ERO1A is required for proper immunoglobulin folding and is retained in the ER via ERP44.
    reference_section_type: RESULTS
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: Reactome:R-HSA-3341296
  title: Reactome ER-lumen oxidative folding annotation for ERO1A
  findings: []
- id: file:human/ERO1A/ERO1A-uniprot.txt
  title: UniProt entry Q96HE7 (ERO1A_HUMAN), ERO1-like protein alpha
  findings:
  - statement: FAD-dependent ER sulfhydryl oxidase (EC 1.8.3.2) that reoxidizes P4HB/PDI to drive disulfide-bond formation and passes electrons to O2 generating H2O2; peripheral ER membrane protein on the lumenal side retained by ERP44; activity tightly regulated by regulatory disulfides and FAM20C phosphorylation; hypoxia-induced.
    reference_section_type: OTHER
- id: file:human/ERO1A/ERO1A-deep-research-falcon.md
  title: Falcon deep research report for ERO1A
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: "LLM-synthesized (Edison Scientific Literature) review-of-reviews; cites secondary review articles (Chen 2024 JECCR, Jha 2021 ARS, Zito 2024 BBA, Moilanen 2018 LSA, He 2025) by author-year/DOI keys rather than PMIDs, so individual cited claims were not verified against cached publications. The core mechanistic picture (FAD-dependent reoxidation of PDI with O2 as terminal acceptor and H2O2 as byproduct; HIF-1alpha/UPR induction; PDI substrate selectivity; IP3R/RyR Ca2+ regulation) is consistent with UniProt and the cached primary literature and is used here only to corroborate, not to override, existing experimental annotations. Some claims (e.g. MAM enrichment, '~25% of cellular H2O2', specific Kd values, cancer/therapeutic content) are not independently checked and are not used to add or remove annotations."
  findings:
  - statement: ERO1A re-oxidizes reduced PDI by accepting electrons through its FAD cofactor, with molecular oxygen as the terminal electron acceptor, producing H2O2; it binds PDI with highest affinity (Kd 1.7 uM) relative to other ER thiol isomerases, and is induced by HIF-1alpha under hypoxia and by the PERK-eIF2alpha-ATF4-CHOP UPR branch.
    reference_section_type: RESULTS
core_functions:
- description: FAD-dependent endoplasmic-reticulum sulfhydryl oxidase that reoxidizes the protein disulfide isomerase P4HB/PDI, regenerating PDI's active site so it can catalyze further disulfide-bond formation in secretory proteins, with electrons passed via FAD to O2 producing H2O2.
  molecular_function:
    id: GO:0016971
    label: flavin-dependent sulfhydryl oxidase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
    supporting_text: Efficiently reoxidizes P4HB/PDI, the enzyme catalyzing protein disulfide formation, in order to allow P4HB to sustain additional rounds of disulfide formation.
  - reference_id: PMID:11707400
    supporting_text: both human Ero1-Lalpha and Ero1-Lbeta (hEROs) facilitate disulfide bond formation in immunoglobulin subunits by selectively oxidizing PDI
- description: Sets and balances the redox state of the ER lumen, with activity tightly regulated by intramolecular regulatory disulfides (and FAM20C phosphorylation) to sustain oxidative protein folding while limiting reactive-oxygen-species accumulation.
  molecular_function:
    id: GO:0016971
    label: flavin-dependent sulfhydryl oxidase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/ERO1A/ERO1A-uniprot.txt
    supporting_text: Enzyme activity is tightly regulated to prevent the accumulation of reactive oxygen species in the endoplasmic reticulum.
  directly_involved_in:
  - id: GO:0045454
    label: cell redox homeostasis
proposed_new_terms: []
suggested_questions:
- question: How is ERO1A activity coordinated with ERO1B and with PRDX4/peroxiredoxin-based H2O2 clearance to balance oxidative folding capacity against oxidative damage in different secretory tissues?
- question: What is the in vivo significance of the secreted/Golgi pools of ERO1A relative to its ER-lumenal oxidase role, and is FAM20C phosphorylation the main switch controlling them?
suggested_experiments:
- description: Reconstitute the ERO1A-PDI oxidation cycle in vitro with purified FAD-loaded ERO1A and P4HB, measuring O2 consumption and H2O2 production to quantify catalytic turnover and the effect of the regulatory disulfides and S145 phosphorylation.
- description: CRISPR knockout of ERO1A (and double knockout with ERO1B) in antibody-secreting cells followed by redox proteomics and immunoglobulin folding/secretion assays to define non-redundant substrate requirements.