WFS1

id: O76024
gene_symbol: WFS1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Wolframin (WFS1) is a multi-pass transmembrane glycoprotein primarily localized
  to the
  endoplasmic reticulum (ER) membrane and mitochondria-associated ER membranes (MAMs).
  The protein plays essential roles in ER calcium homeostasis by positively modulating
  ER Ca2+ levels through increasing the rate of Ca2+ uptake [PMID:16989814]. WFS1
  also
  functions as a negative regulator of ER stress signaling, particularly by suppressing
  ATF6alpha-mediated unfolded protein response through stabilization of the E3 ubiquitin
  ligase HRD1 and promotion of ATF6alpha proteasomal degradation [PMID:20160352].
  Additionally, WFS1 interacts with and stabilizes V-ATPase subunit ATP6V1A and
  Na+/K+-ATPase beta1 subunit (ATP1B1), regulating their expression and stability
  [PMID:23035048, PMID:17947299]. Mutations in WFS1 cause Wolfram syndrome (DIDMOAD
  -
  diabetes insipidus, diabetes mellitus, optic atrophy, deafness), characterized by
  progressive beta-cell loss and neurodegeneration due to dysregulated ER stress and
  calcium homeostasis.
existing_annotations:
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      WFS1 is directly involved in the UPR, functioning as a negative regulator
      of
      ER stress signaling. WFS1 suppresses expression of ATF6alpha target genes
      and
      represses ATF6alpha-mediated activation of the ER stress response element
      promoter
      [PMID:20160352]. WFS1 expression is transcriptionally upregulated by ER stress,
      indicating it is part of the ER stress response machinery [PMID:15994758].
    action: ACCEPT
    reason: >-
      Core function supported by phylogenetic analysis (IBA) and extensive experimental
      evidence. WFS1 negatively regulates the UPR through ATF6alpha suppression
      and is
      induced by ER stress [PMID:20160352, PMID:15994758].
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 negatively regulates a key transcription factor involved
        in ER stress signaling, activating transcription factor 6alpha (ATF6alpha),
        through the ubiquitin-proteasome pathway"
    - reference_id: PMID:15994758
      supporting_text: "WFS1 expression was transcriptionally up-regulated by ER stress-inducing
        chemical insults"
    - reference_id: file:human/WFS1/WFS1-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      WFS1 is an ER membrane-resident multi-pass transmembrane protein. This localization
      has been confirmed by multiple studies using immunocytochemistry, subcellular
      fractionation, and electron microscopy [PMID:14527944, PMID:11181571, PMID:23035048].
    action: ACCEPT
    reason: >-
      Core localization consistently demonstrated across multiple independent studies.
      UniProt annotation confirms ER membrane localization with multi-pass topology.
    supported_by:
    - reference_id: PMID:14527944
      supporting_text: "Endoglycosidase H digestion, immunocytochemistry, and subcellular
        fractionation studies all indicated that wolframin is localized to the endoplasmic
        reticulum"
    - reference_id: PMID:11181571
      supporting_text: "predominant subcellular localization to endoplasmic reticulum
        in cultured cells"
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      WFS1 participates in the regulation of cellular Ca2+ homeostasis by modulating
      the filling state of the ER Ca2+ store. Studies demonstrate WFS1 positively
      modulates ER Ca2+ levels by increasing the rate of Ca2+ uptake, and the magnitude
      of store-operated Ca2+ entry parallels WFS1 expression levels [PMID:16989814].
    action: ACCEPT
    reason: >-
      Core function supported by phylogenetic inference and direct experimental
      evidence.
      WFS1 regulates ER calcium homeostasis, a central aspect of its physiological
      role.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein to positively modulate ER Ca(2+) levels by increasing
        the rate of Ca(2+) uptake"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation inferring ER localization from InterPro domain mapping and
      orthology. This is consistent with experimental data showing ER localization.
    action: ACCEPT
    reason: >-
      Computational inference consistent with extensive experimental evidence of
      ER
      localization [PMID:14527944, PMID:11181571]. The more specific term
      GO:0005789 (ER membrane) is also correctly annotated.
    supported_by:
    - reference_id: PMID:14527944
      supporting_text: "wolframin is localized to the endoplasmic reticulum in rat
        brain hippocampus and rat pancreatic islet beta-cells"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation based on UniProtKB subcellular location mapping. Consistent
      with
      experimental evidence and IBA annotation.
    action: ACCEPT
    reason: >-
      Computational annotation correctly reflects the established ER membrane
      localization of this multi-pass transmembrane protein.
    supported_by:
    - reference_id: PMID:11181571
      supporting_text: "predominant subcellular localization to endoplasmic reticulum
        in cultured cells"
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA machine learning annotation. While WFS1 does affect gene expression
      indirectly through its regulation of ATF6alpha signaling, this term is
      too general and does not capture the mechanistic specificity.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is an indirect effect of WFS1's role in ER stress signaling. The more
      specific annotation of negative regulation of ATF6-mediated UPR is more
      informative. This general term is not wrong but represents an overly broad
      annotation.
- term:
    id: GO:0030133
    label: transport vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation based on UniProtKB subcellular location vocabulary. WFS1 has
      been shown to localize to secretory granules in addition to ER [PMID:23035048].
    action: KEEP_AS_NON_CORE
    reason: >-
      WFS1 localization to secretory granules has been demonstrated, but this is
      secondary to its primary ER membrane localization. The term captures a valid
      but non-core aspect of WFS1 localization.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "WFS1 also localizes to secretory granules in human neuroblastoma
        cells"
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProtKB keyword mapping. This is consistent with the
      secretory granule localization observed for WFS1.
    action: KEEP_AS_NON_CORE
    reason: >-
      A broad term that encompasses the secretory granule localization. Not incorrect
      but less specific than GO:0030141 (secretory granule).
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA machine learning annotation. WFS1 does participate in ER stress signaling,
      but this term is very broad and non-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This term is too general. WFS1's role in signaling is specifically in negative
      regulation of ER stress/UPR signaling, which is captured by more specific
      terms.
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro domain mapping. Consistent with experimental
      evidence of WFS1's role in calcium homeostasis.
    action: ACCEPT
    reason: >-
      Duplicate with IBA annotation above. Both correctly reflect WFS1's core
      function in calcium homeostasis. The IBA annotation provides stronger
      phylogenetic support.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein participates in the regulation of cellular Ca(2+)
        homeostasis"
- term:
    id: GO:1902532
    label: negative regulation of intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA annotation. WFS1 does negatively regulate ER stress signaling, but this
      term is overly broad.
    action: KEEP_AS_NON_CORE
    reason: >-
      The more specific term GO:1903573 (negative regulation of response to ER stress)
      better captures WFS1's function. This general term is not wrong but is less
      informative.
- term:
    id: GO:1903573
    label: negative regulation of response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      ARBA annotation correctly identifying WFS1's role as a negative regulator
      of
      ER stress response. This is well-supported by experimental evidence [PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function of WFS1. Directly supported by experimental evidence showing
      WFS1 negatively regulates ATF6-mediated ER stress signaling.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 negatively regulates a key transcription factor involved
        in ER stress signaling"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17947299
  review:
    summary: >-
      IPI based on co-immunoprecipitation showing WFS1 interacts with Na+/K+ ATPase
      beta1 subunit (ATP1B1). However, 'protein binding' is uninformative.
    action: MODIFY
    reason: >-
      The generic 'protein binding' term provides no functional insight. This should
      be replaced with a more specific binding term if available, or the interaction
      should be captured as part of the stabilization/regulation function.
    proposed_replacement_terms:
    - id: GO:0051117
      label: ATPase binding
    supported_by:
    - reference_id: PMID:17947299
      supporting_text: "We confirmed the interaction by co-immunoprecipitation in
        mammalian cells and with endogenous proteins"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    summary: >-
      From genome-wide YFP fluorescence complementation screen for telomere signaling
      regulators. This is a high-throughput study with potential false positives.
    action: REMOVE
    reason: >-
      Generic 'protein binding' from high-throughput screen. The connection to
      telomere signaling is not a core WFS1 function and may represent noise
      from the screen.
    supported_by:
    - reference_id: PMID:21044950
      supporting_text: Epub 2010 Nov 2. Genome-wide YFP fluorescence 
        complementation screen identifies new regulators for telomere signaling 
        in human cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25274773
  review:
    summary: >-
      IPI showing WFS1 interaction with SERCA (ATP2A2). This is a functionally
      relevant interaction for calcium homeostasis.
    action: MODIFY
    reason: >-
      Generic 'protein binding' should be replaced with more specific term reflecting
      the functional significance of SERCA interaction in calcium homeostasis.
    proposed_replacement_terms:
    - id: GO:0051117
      label: ATPase binding
    supported_by:
    - reference_id: PMID:25274773
      supporting_text: Sarco(endo)plasmic reticulum ATPase is a molecular 
        partner of Wolfram syndrome 1 protein, which negatively regulates its 
        expression.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      From reference map of human binary protein interactome. High-throughput
      interactome study.
    action: REMOVE
    reason: >-
      Generic 'protein binding' from high-throughput interactome study. Multiple
      interactors listed without functional validation. Does not provide
      informative annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein 
        interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      Interactome mapping in neurodegenerative disease context. High-throughput
      study.
    action: REMOVE
    reason: >-
      Generic 'protein binding' from high-throughput study. Does not add functional
      information beyond what is captured by more specific binding annotations.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of 
        Neurodegenerative Disease Proteins and Uncovers Widespread Protein 
        Aggregation in Affected Brains.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 indirectly affects transcription through
      ATF6alpha regulation, but this is not a direct transcriptional regulatory
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is an indirect effect mediated through ATF6alpha suppression. WFS1 is
      not
      a direct transcriptional regulator but affects transcription through ER stress
      signaling modulation.
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 has EF-hand-like domains that could
      potentially bind calmodulin, but direct evidence is limited.
    action: UNDECIDED
    reason: >-
      The EF-hand-like domain in WFS1 suggests calcium-binding capability, but
      direct evidence for calmodulin binding is not available in the reviewed
      literature. Requires experimental validation.
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 is expressed in neurons and localizes
      to secretory granules, but synaptic vesicle membrane localization is not
      directly demonstrated for human WFS1.
    action: UNDECIDED
    reason: >-
      While WFS1 is expressed in neurons and has been shown in secretory granules,
      specific synaptic vesicle membrane localization needs direct experimental
      verification in human cells.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. Consistent with IBA annotation and
      experimental evidence.
    action: ACCEPT
    reason: >-
      Duplicate of IBA annotation. Core function well-supported by experimental
      evidence [PMID:20160352].
- term:
    id: GO:0031016
    label: pancreas development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 is expressed in pancreatic beta-cells
      and mutations cause diabetes, but direct involvement in pancreas development
      is not established.
    action: KEEP_AS_NON_CORE
    reason: >-
      WFS1 mutations affect beta-cell survival and function, but this is distinct
      from a developmental role. The phenotype in Wolfram syndrome is degenerative
      rather than developmental.
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from combined automated annotation. WFS1 enhances ATF6alpha ubiquitination
      through HRD1 stabilization [PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function. WFS1 stabilizes HRD1 E3 ubiquitin ligase and enhances ATF6alpha
      ubiquitination, directly promoting protein ubiquitination.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha
        to the proteasome, and enhanced its ubiquitination"
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 interacts with and stabilizes the
      E3 ubiquitin ligase HRD1 [PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function. WFS1 binds and stabilizes HRD1, an E3 ubiquitin ligase involved
      in ERAD. This interaction is central to WFS1's function in ER stress regulation.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1"
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 is induced by and responds to ER stress
      [PMID:15994758].
    action: ACCEPT
    reason: >-
      Core function. WFS1 expression is induced by ER stress and it functions as
      a negative regulator of the ER stress response.
    supported_by:
    - reference_id: PMID:15994758
      supporting_text: "WFS1 expression was transcriptionally up-regulated by ER stress-inducing
        chemical insults"
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from combined automated annotation. WFS1 participates in ERAD through
      HRD1 stabilization and promotion of ATF6alpha degradation [PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function. WFS1 is involved in ERAD by stabilizing HRD1 and promoting
      proteasomal degradation of ATF6alpha.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha
        to the proteasome, and enhanced its ubiquitination and proteasome-mediated
        degradation"
- term:
    id: GO:0042048
    label: olfactory behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. No direct evidence for WFS1 involvement
      in olfactory behavior in humans.
    action: REMOVE
    reason: >-
      No literature support for this annotation. Wolfram syndrome phenotype does
      not include olfactory dysfunction. This may be an over-inference from
      ortholog data.
- term:
    id: GO:0045927
    label: positive regulation of growth
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 affects cell survival through ER
      stress regulation, but positive regulation of growth is not a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is likely an indirect effect of WFS1's role in cell survival and ER
      stress. Not a primary function of the protein.
- term:
    id: GO:0048306
    label: calcium-dependent protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 has EF-hand-like domains that may
      enable calcium-dependent protein interactions.
    action: UNDECIDED
    reason: >-
      The EF-hand-like domain suggests potential calcium-dependent binding, but
      direct experimental evidence for this specific molecular function is not
      available in the reviewed literature.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from combined automated annotation. WFS1 stabilizes V-ATPase subunit
      ATP6V1A, Na+/K+-ATPase beta1 subunit, and HRD1 [PMID:23035048, PMID:17947299,
      PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function. WFS1 stabilizes multiple protein partners through
      proteasome-independent mechanisms [PMID:23035048].
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "WFS1 protein deficiency affects... Protein stability assays
        demonstrated that the V1A subunit was degraded more rapidly in WFS1 depleted
        neuroblastoma cells"
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1"
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from combined automated annotation. WFS1 interacts with V-ATPase V1A
      subunit and Na+/K+-ATPase beta1 subunit [PMID:23035048, PMID:17947299].
    action: ACCEPT
    reason: >-
      Core molecular function. WFS1 binds to and regulates multiple ATPase subunits
      including V-ATPase and Na+/K+-ATPase.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "We demonstrated a novel interaction between WFS1 and the V1A
        subunit of the H(+) V-ATPase"
    - reference_id: PMID:17947299
      supporting_text: "Na+/K+ ATPase beta1 subunit was identified as an interacting
        clone"
- term:
    id: GO:0070628
    label: proteasome binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 brings ATF6alpha to the proteasome
      [PMID:20160352], suggesting proteasome interaction.
    action: ACCEPT
    reason: >-
      WFS1 brings substrates to the proteasome for degradation, indicating
      proteasome binding activity.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "brought ATF6alpha to the proteasome"
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 interacts with ATF6alpha, a
      transcription factor, to promote its degradation [PMID:20160352].
    action: ACCEPT
    reason: >-
      WFS1 binds to ATF6alpha, a DNA-binding transcription factor, to target
      it for proteasomal degradation.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 negatively regulates a key transcription factor... brought
        ATF6alpha to the proteasome"
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic
      apoptotic signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. WFS1 deficiency leads to increased
      apoptosis through uncontrolled ER stress [PMID:16087305, PMID:20160352].
    action: ACCEPT
    reason: >-
      WFS1 protects cells from ER stress-induced apoptosis by negatively regulating
      ER stress signaling.
    supported_by:
    - reference_id: PMID:16087305
      supporting_text: "we found no increased apoptosis following induction of ER
        stress but rather by staurosporine treatment in the absence of WFS1 function.
        This indicates a new role of WFS1 deficiency in programmed cell death"
- term:
    id: GO:1903892
    label: negative regulation of ATF6-mediated unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Ensembl Compara ortholog transfer. This is a core function of WFS1
      [PMID:20160352].
    action: ACCEPT
    reason: >-
      Core function. WFS1 specifically negatively regulates ATF6alpha-mediated UPR
      through proteasomal degradation of ATF6alpha.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 negatively regulates a key transcription factor involved
        in ER stress signaling, activating transcription factor 6alpha (ATF6alpha)"
- term:
    id: GO:2000675
    label: negative regulation of type B pancreatic cell apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA from combined automated annotation. WFS1 deficiency causes beta-cell
      death in Wolfram syndrome [PMID:16087305].
    action: ACCEPT
    reason: >-
      Core function in beta-cells. WFS1 protects pancreatic beta-cells from
      apoptosis, and its deficiency causes progressive beta-cell loss.
    supported_by:
    - reference_id: PMID:16087305
      supporting_text: "Mice lacking the WFS1 gene display degeneration of pancreatic
        beta-cells following induction of ER stress"
- term:
    id: GO:0006983
    label: ER overload response
  evidence_type: IDA
  original_reference_id: PMID:16989814
  review:
    summary: >-
      IDA from direct experiments showing WFS1 modulates ER calcium and is involved
      in ER stress response [PMID:16989814].
    action: ACCEPT
    reason: >-
      Core function. WFS1 is involved in ER calcium homeostasis and ER stress
      response, which includes ER overload response.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein participates in the regulation of cellular Ca(2+)
        homeostasis, at least partly, by modulating the filling state of the ER Ca(2+)
        store"
- term:
    id: GO:0140597
    label: protein carrier chaperone
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      IDA annotation. WFS1 brings ATF6alpha to the proteasome for degradation,
      which could be considered a carrier function.
    action: KEEP_AS_NON_CORE
    reason: >-
      While WFS1 does transport ATF6alpha to the proteasome, "chaperone" is not
      the most accurate descriptor. WFS1's primary function is as a negative
      regulator of ER stress rather than a classic chaperone.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: Wolfram syndrome 1 gene negatively regulates ER stress 
        signaling in rodent and human cells.
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation based on manual transfer from ortholog. Consistent with
      experimental evidence [PMID:20160352].
    action: ACCEPT
    reason: >-
      Duplicate of IEA annotation. Core function supported by experimental
      evidence showing WFS1 enhances ATF6alpha ubiquitination.
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      Direct experimental evidence showing WFS1 enhances ATF6alpha ubiquitination
      through HRD1 stabilization.
    action: ACCEPT
    reason: >-
      Core function with strong experimental support.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "enhanced its ubiquitination and proteasome-mediated degradation"
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation. Consistent with experimental evidence of WFS1 role in ERAD.
    action: ACCEPT
    reason: >-
      Duplicate of IEA annotation. Core function in ERAD pathway.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      Direct experimental evidence showing WFS1 participates in ERAD through
      HRD1 stabilization and ATF6alpha degradation.
    action: ACCEPT
    reason: >-
      Core function with strong experimental support.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha
        to the proteasome, and enhanced its ubiquitination and proteasome-mediated
        degradation"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23035048
  review:
    summary: >-
      IPI showing WFS1 interacts with V-ATPase V1A subunit (ATP6V1A). Functionally
      relevant interaction.
    action: MODIFY
    reason: >-
      Generic 'protein binding' should be replaced with more specific term.
      The interaction with V-ATPase is functionally important.
    proposed_replacement_terms:
    - id: GO:0051117
      label: ATPase binding
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "We demonstrated a novel interaction between WFS1 and the V1A
        subunit of the H(+) V-ATPase"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23035048
  review:
    summary: >-
      Direct experimental evidence confirming ER localization using immunofluorescence
      and electron microscopy.
    action: ACCEPT
    reason: >-
      Core localization confirmed by multiple experimental approaches.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "immunofluorescent and electron-microscopy analyses confirmed
        that WFS1 also localizes to secretory granules in human neuroblastoma cells"
- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IDA
  original_reference_id: PMID:23035048
  review:
    summary: >-
      Direct experimental evidence showing WFS1 localization to secretory granules
      in neuroblastoma cells and pancreatic beta-cells.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid localization but secondary to primary ER membrane localization.
      Functionally relevant for V-ATPase interaction in granular acidification.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "immunofluorescent and electron-microscopy analyses confirmed
        that WFS1 also localizes to secretory granules in human neuroblastoma cells"
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:23035048
  review:
    summary: >-
      IMP based on WFS1 depletion experiments showing inverse association between
      p21 expression and apoptosis.
    action: ACCEPT
    reason: >-
      Core function. WFS1 protects cells from apoptosis through multiple mechanisms
      including ER stress regulation.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "Cell cycle assays measuring p21(cip) showed reduced levels
        in WFS1 depleted cells, and an inverse association between p21(cip) expression
        and apoptosis"
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:23035048
  review:
    summary: >-
      IMP showing WFS1 depletion leads to faster degradation of V1A subunit.
    action: ACCEPT
    reason: >-
      Core function. WFS1 stabilizes V-ATPase V1A subunit and other proteins
      through proteasome-independent mechanisms.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "Protein stability assays demonstrated that the V1A subunit
        was degraded more rapidly in WFS1 depleted neuroblastoma cells compared with
        wild-type"
- term:
    id: GO:1903573
    label: negative regulation of response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:23035048
  review:
    summary: >-
      IMP from WFS1 depletion studies showing effects on ER stress response.
    action: ACCEPT
    reason: >-
      Core function. WFS1 negatively regulates ER stress response, and its
      depletion leads to dysregulated ER stress signaling.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: "WFS1 protein deficiency affects the unfolded protein response"
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation from ortholog transfer. Consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      Duplicate annotation. Core function well-supported.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      IDA showing WFS1 stabilizes HRD1 E3 ubiquitin ligase.
    action: ACCEPT
    reason: >-
      Core function. WFS1 stabilizes HRD1, preventing its degradation.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1"
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS annotation from review article on ER stress and HRD1 in neurodegeneration.
    action: ACCEPT
    reason: >-
      Consistent with experimental evidence from multiple primary studies.
    supported_by:
    - reference_id: PMID:23710284
      supporting_text: "Apr 18. Endoplasmic reticulum stress and Parkinson's disease:
        the role of HRD1 in averting apoptosis in neurodegenerative disease."
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  review:
    summary: >-
      Reactome pathway annotation for FAM20C phosphorylation substrates. WFS1 is
      phosphorylated in the ER lumen.
    action: KEEP_AS_NON_CORE
    reason: >-
      WFS1 is primarily an ER membrane protein with portions in the lumen.
      The phosphorylation site is in the luminal portion. This is a valid but
      secondary localization annotation.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      IDA showing WFS1 suppresses ATF6alpha target gene expression.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is an indirect effect of WFS1's negative regulation of ATF6alpha.
      WFS1 is not a direct transcriptional regulator but affects transcription
      through ATF6alpha degradation.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 suppressed expression of ATF6alpha target genes and repressed
        ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:20160352
  review:
    summary: >-
      NAS annotation for ER membrane localization. Consistent with other evidence.
    action: ACCEPT
    reason: >-
      Core localization. Consistent with extensive experimental evidence.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: Wolfram syndrome 1 gene negatively regulates ER stress 
        signaling in rodent and human cells.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      IDA showing WFS1 binds and stabilizes HRD1 E3 ubiquitin ligase.
    action: ACCEPT
    reason: >-
      Core molecular function. WFS1 binds HRD1 and stabilizes it.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1"
- term:
    id: GO:1903892
    label: negative regulation of ATF6-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:20160352
  review:
    summary: >-
      Direct experimental evidence showing WFS1 negatively regulates ATF6alpha
      signaling through proteasomal degradation.
    action: ACCEPT
    reason: >-
      Core function with strong experimental support.
    supported_by:
    - reference_id: PMID:20160352
      supporting_text: "WFS1 negatively regulates a key transcription factor involved
        in ER stress signaling, activating transcription factor 6alpha (ATF6alpha),
        through the ubiquitin-proteasome pathway"
- term:
    id: GO:2000675
    label: negative regulation of type B pancreatic cell apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:16087305
  review:
    summary: >-
      IMP showing WFS1 deficiency leads to beta-cell degeneration following ER stress.
    action: ACCEPT
    reason: >-
      Core function in beta-cells. WFS1 protects pancreatic beta-cells from
      apoptosis.
    supported_by:
    - reference_id: PMID:16087305
      supporting_text: "Mice lacking the WFS1 gene display degeneration of pancreatic
        beta-cells following induction of ER stress"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791169
  review:
    summary: >-
      Reactome pathway annotation for WFS1 expression. Consistent with other evidence.
    action: ACCEPT
    reason: >-
      Core localization. Consistent with extensive experimental evidence.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from ortholog transfer. Consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      Core localization. Multiple annotations with different evidence codes
      all support ER localization.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:15994758
  review:
    summary: >-
      Direct experimental evidence showing WFS1 expression is induced by ER stress.
    action: ACCEPT
    reason: >-
      Core function. WFS1 is part of the ER stress response machinery.
    supported_by:
    - reference_id: PMID:15994758
      supporting_text: "WFS1 expression was transcriptionally up-regulated by ER stress-inducing
        chemical insults"
- term:
    id: GO:0045927
    label: positive regulation of growth
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from ortholog transfer. WFS1 promotes cell survival but direct positive
      regulation of growth is not a primary function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an indirect effect. WFS1's primary role is in ER stress regulation
      and cell survival, not growth regulation per se.
- term:
    id: GO:0006983
    label: ER overload response
  evidence_type: TAS
  original_reference_id: PMID:17947299
  review:
    summary: >-
      TAS annotation. WFS1 is involved in ER stress response.
    action: ACCEPT
    reason: >-
      Core function. WFS1 is involved in ER homeostasis and stress response.
    supported_by:
    - reference_id: PMID:17947299
      supporting_text: "Wolframin deficiency increases ER stress"
- term:
    id: GO:0007601
    label: visual perception
  evidence_type: IMP
  original_reference_id: PMID:9771706
  review:
    summary: >-
      IMP based on optic atrophy in Wolfram syndrome patients with WFS1 mutations.
      This is a disease phenotype rather than a direct molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      This reflects the disease phenotype (optic atrophy) in Wolfram syndrome
      rather than a direct functional role of WFS1 in visual perception. The
      visual defect is secondary to retinal ganglion cell degeneration.
    supported_by:
    - reference_id: PMID:9771706
      supporting_text: A gene encoding a transmembrane protein is mutated in 
        patients with diabetes mellitus and optic atrophy (Wolfram syndrome).
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: IMP
  original_reference_id: PMID:17492394
  review:
    summary: >-
      IMP based on hearing loss associated with WFS1 mutations. Disease phenotype.
    action: KEEP_AS_NON_CORE
    reason: >-
      This reflects the deafness phenotype in Wolfram syndrome and DFNA6, not
      a direct role of WFS1 in auditory function. The hearing loss is likely
      secondary to hair cell or neuronal dysfunction.
    supported_by:
    - reference_id: PMID:17492394
      supporting_text: Mutations in the WFS1 gene are a frequent cause of 
        autosomal dominant nonsyndromic low-frequency hearing loss in Japanese.
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IDA
  original_reference_id: PMID:16989814
  review:
    summary: >-
      Direct experimental evidence showing WFS1 modulates ER Ca2+ levels by
      increasing the rate of Ca2+ uptake.
    action: ACCEPT
    reason: >-
      Core function. This is more specific than general calcium ion homeostasis
      and precisely describes WFS1's role in ER calcium regulation.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein to positively modulate ER Ca(2+) levels by increasing
        the rate of Ca(2+) uptake"
- term:
    id: GO:0043069
    label: negative regulation of programmed cell death
  evidence_type: IMP
  original_reference_id: PMID:9771706
  review:
    summary: >-
      IMP from WFS1 mutations causing cell death in Wolfram syndrome.
    action: ACCEPT
    reason: >-
      Core function. WFS1 protects cells from apoptosis through ER stress
      regulation and calcium homeostasis.
    supported_by:
    - reference_id: PMID:9771706
      supporting_text: A gene encoding a transmembrane protein is mutated in 
        patients with diabetes mellitus and optic atrophy (Wolfram syndrome).
- term:
    id: GO:0043524
    label: negative regulation of neuron apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:9771706
  review:
    summary: >-
      IMP from neurodegeneration in Wolfram syndrome.
    action: ACCEPT
    reason: >-
      Core function in neurons. WFS1 protects neurons from apoptosis, and its
      deficiency causes neurodegeneration.
    supported_by:
    - reference_id: PMID:9771706
      supporting_text: A gene encoding a transmembrane protein is mutated in 
        patients with diabetes mellitus and optic atrophy (Wolfram syndrome).
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:17947299
  review:
    summary: >-
      IPI showing WFS1 interacts with Na+/K+ ATPase beta1 subunit.
    action: ACCEPT
    reason: >-
      Core molecular function. WFS1 binds to and stabilizes Na+/K+ ATPase subunits.
    supported_by:
    - reference_id: PMID:17947299
      supporting_text: "Na+/K+ ATPase beta1 subunit was identified as an interacting
        clone"
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:17947299
  review:
    summary: >-
      IDA based on WFS1's role in stabilizing ATPase subunits.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a broad term. The more specific terms about protein stabilization
      and ERAD pathway are more informative.
    supported_by:
    - reference_id: PMID:17947299
      supporting_text: Oct 18. Sodium-potassium ATPase 1 subunit is a molecular 
        partner of Wolframin, an endoplasmic reticulum protein involved in ER 
        stress.
- term:
    id: GO:0051928
    label: positive regulation of calcium ion transport
  evidence_type: IDA
  original_reference_id: PMID:16989814
  review:
    summary: >-
      IDA showing WFS1 positively modulates ER Ca2+ levels by increasing the
      rate of Ca2+ uptake.
    action: ACCEPT
    reason: >-
      Core function. WFS1 promotes calcium uptake into the ER.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein to positively modulate ER Ca(2+) levels by increasing
        the rate of Ca(2+) uptake"
- term:
    id: GO:0001822
    label: kidney development
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP based on diabetes insipidus in Wolfram syndrome, suggesting kidney
      dysfunction.
    action: KEEP_AS_NON_CORE
    reason: >-
      This reflects the diabetes insipidus phenotype, which may indicate a role
      in kidney function but is not a direct developmental role. More likely
      reflects cellular dysfunction rather than developmental function.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0003091
    label: renal water homeostasis
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP based on diabetes insipidus phenotype in Wolfram syndrome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the diabetes insipidus phenotype. WFS1 may affect vasopressin
      secretion or response through its general cellular functions, but this
      is not a direct molecular function.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:11181571
  review:
    summary: >-
      Direct immunocytochemistry evidence showing ER membrane localization.
    action: ACCEPT
    reason: >-
      Core localization with strong experimental support.
    supported_by:
    - reference_id: PMID:11181571
      supporting_text: "predominant subcellular localization to endoplasmic reticulum
        in cultured cells"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:14527944
  review:
    summary: >-
      IDA from subcellular fractionation and immunocytochemistry studies.
    action: ACCEPT
    reason: >-
      Core localization with strong experimental support.
    supported_by:
    - reference_id: PMID:14527944
      supporting_text: "wolframin is localized to the endoplasmic reticulum in rat
        brain hippocampus and rat pancreatic islet beta-cells"
- term:
    id: GO:0007601
    label: visual perception
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP based on optic atrophy in Wolfram syndrome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Disease phenotype reflecting neurodegeneration rather than direct
      function in visual perception.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: PMID:11181571
  review:
    summary: >-
      ISS suggesting dendritic localization based on neuronal expression.
    action: KEEP_AS_NON_CORE
    reason: >-
      WFS1 is expressed in neurons and may localize to dendrites, but primary
      localization is ER membrane. Neuronal expression is important for
      understanding the neurodegeneration phenotype.
    supported_by:
    - reference_id: PMID:11181571
      supporting_text: 'WFS1 (Wolfram syndrome 1) gene product: predominant subcellular
        localization to endoplasmic reticulum in cultured cells and neuronal expression
        in rat brain.'
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP based on diabetes mellitus phenotype in Wolfram syndrome.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the diabetes phenotype due to beta-cell dysfunction. WFS1 affects
      glucose homeostasis indirectly through its role in beta-cell survival
      rather than direct glucose regulation.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0043524
    label: negative regulation of neuron apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP from neurodegeneration observed in Wolfram syndrome.
    action: ACCEPT
    reason: >-
      Core function. Duplicate annotation. WFS1 protects neurons from apoptosis.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0050877
    label: nervous system process
  evidence_type: IMP
  original_reference_id: PMID:9817917
  review:
    summary: >-
      IMP based on neurological symptoms in Wolfram syndrome.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This term is too broad. The neurological effects in Wolfram syndrome are
      due to neurodegeneration, which is captured by more specific terms about
      negative regulation of apoptosis.
    supported_by:
    - reference_id: PMID:9817917
      supporting_text: Diabetes insipidus, diabetes mellitus, optic atrophy and 
        deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) 
        coding for a predicted transmembrane protein.
- term:
    id: GO:0055074
    label: calcium ion homeostasis
  evidence_type: IDA
  original_reference_id: PMID:14527944
  review:
    summary: >-
      Direct experimental evidence showing wolframin expression increases
      intracellular calcium.
    action: ACCEPT
    reason: >-
      Core function. WFS1 is involved in calcium homeostasis through ion
      channel activity in ER membranes.
    supported_by:
    - reference_id: PMID:14527944
      supporting_text: "Wolframin thus appears to be important in the regulation of
        intracellular Ca2+ homeostasis"
- term:
    id: GO:0005261
    label: monoatomic cation channel activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:16989814
      supporting_text: "WFS1 protein to positively modulate ER Ca(2+) levels by increasing
        the rate of Ca(2+) uptake"
    - reference_id: PMID:14527944
      supporting_text: "Wolframin thus appears to be important in the regulation of
        intracellular Ca2+ homeostasis"
core_functions:
- description: >-
    Regulation of ER calcium homeostasis by modulating the filling state of
    the ER Ca2+ store through increased rate of Ca2+ uptake, potentially via
    cation channel activity in ER membranes
  molecular_function:
    id: GO:0005261
    label: monoatomic cation channel activity
  supported_by:
  - reference_id: PMID:16989814
    supporting_text: "WFS1 protein to positively modulate ER Ca(2+) levels by increasing
      the rate of Ca(2+) uptake"
  - reference_id: PMID:14527944
    supporting_text: "Wolframin thus appears to be important in the regulation of
      intracellular Ca2+ homeostasis"
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0055074
    label: calcium ion homeostasis
  - id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
- description: >-
    Negative regulation of ER stress signaling through binding and targeting
    ATF6alpha transcription factor for proteasomal degradation
  molecular_function:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  supported_by:
  - reference_id: PMID:20160352
    supporting_text: "WFS1 negatively regulates a key transcription factor involved
      in ER stress signaling, activating transcription factor 6alpha (ATF6alpha),
      through the ubiquitin-proteasome pathway"
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  - id: GO:1903573
    label: negative regulation of response to endoplasmic reticulum stress
  - id: GO:1903892
    label: negative regulation of ATF6-mediated unfolded protein response
- description: >-
    ATPase binding and stabilization, including V-ATPase V1A subunit and
    Na+/K+-ATPase beta1 subunit, regulating their expression and stability
  molecular_function:
    id: GO:0051117
    label: ATPase binding
  supported_by:
  - reference_id: PMID:23035048
    supporting_text: "We demonstrated a novel interaction between WFS1 and the V1A
      subunit of the H(+) V-ATPase"
  - reference_id: PMID:17947299
    supporting_text: "Na+/K+ ATPase beta1 subunit was identified as an interacting
      clone"
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0050821
    label: protein stabilization
- description: >-
    Stabilization of HRD1 E3 ubiquitin ligase and involvement in ERAD pathway,
    promoting ubiquitination of substrates for proteasomal degradation
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  supported_by:
  - reference_id: PMID:20160352
    supporting_text: "WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha
      to the proteasome, and enhanced its ubiquitination"
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  - id: GO:0031398
    label: positive regulation of protein ubiquitination
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:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot 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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11181571
  title: 'WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization
    to endoplasmic reticulum in cultured cells and neuronal expression in rat brain.'
  findings:
  - statement: WFS1 predominantly localizes to the ER in cultured cells
  - statement: Neuronal expression observed in rat brain
- id: PMID:14527944
  title: Wolframin expression induces novel ion channel activity in endoplasmic 
    reticulum membranes and increases intracellular calcium.
  findings:
  - statement: WFS1 is localized to the ER in brain hippocampus and pancreatic 
      beta-cells
  - statement: Reconstitution demonstrated cation-selective ion channel activity
  - statement: WFS1 expression increases cytosolic calcium levels
- id: PMID:15994758
  title: Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic
    beta-cells via transcriptional activation.
  findings:
  - statement: WFS1 expression is induced by ER stress
  - statement: WFS1 is expressed in beta-cells and delta-cells but not 
      alpha-cells
- id: PMID:16087305
  title: Expressional and functional studies of Wolframin, the gene function 
    deficient in Wolfram syndrome, in mice and patient cells.
  findings:
  - statement: WFS1 deficiency causes beta-cell degeneration following ER stress
  - statement: WFS1 deficiency affects programmed cell death
- id: PMID:16989814
  title: WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic
    reticulum.
  findings:
  - statement: WFS1 positively modulates ER Ca2+ levels by increasing Ca2+ 
      uptake rate
  - statement: Store-operated Ca2+ entry parallels WFS1 expression levels
- id: PMID:17492394
  title: Mutations in the WFS1 gene are a frequent cause of autosomal dominant 
    nonsyndromic low-frequency hearing loss in Japanese.
  findings:
  - statement: WFS1 mutations cause low-frequency hearing loss
- id: PMID:17947299
  title: Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, 
    an endoplasmic reticulum protein involved in ER stress.
  findings:
  - statement: WFS1 interacts with Na+/K+ ATPase beta1 subunit
  - statement: Interaction important for ATPase maturation
  - statement: WFS1 deficiency reduces ATPase expression
- id: PMID:20160352
  title: Wolfram syndrome 1 gene negatively regulates ER stress signaling in 
    rodent and human cells.
  findings:
  - statement: WFS1 negatively regulates ATF6alpha through ubiquitin-proteasome 
      pathway
  - statement: WFS1 stabilizes HRD1 E3 ubiquitin ligase
  - statement: WFS1 enhances ATF6alpha ubiquitination and proteasomal 
      degradation
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new 
    regulators for telomere signaling in human cells.
  findings: []
- id: PMID:23035048
  title: Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram 
    syndrome 1 (WFS1) protein, which regulates its expression and stability.
  findings:
  - statement: WFS1 interacts with V-ATPase V1A subunit
  - statement: WFS1 stabilizes V1A subunit through proteasome-independent 
      mechanism
  - statement: WFS1 also localizes to secretory granules
- id: PMID:23710284
  title: 'Endoplasmic reticulum stress and Parkinson''s disease: the role of HRD1
    in averting apoptosis in neurodegenerative disease.'
  findings: []
- id: PMID:25274773
  title: Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram 
    syndrome 1 protein, which negatively regulates its expression.
  findings:
  - statement: WFS1 interacts with SERCA (ATP2A2)
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
    Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:9771706
  title: A gene encoding a transmembrane protein is mutated in patients with 
    diabetes mellitus and optic atrophy (Wolfram Syndrome).
  findings:
  - statement: WFS1 mutations cause Wolfram syndrome
  - statement: Disease characterized by diabetes mellitus and optic atrophy
- id: PMID:9817917
  title: Diabetes insipidus, diabetes mellitus, optic atrophy and deafness 
    (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a 
    predicted transmembrane protein.
  findings:
  - statement: WFS1 mutations cause DIDMOAD (Wolfram syndrome)
  - statement: Gene encodes predicted transmembrane protein
- id: Reactome:R-HSA-1791169
  title: Expression of WFS1
  findings: []
- id: Reactome:R-HSA-8952289
  title: FAM20C phosphorylates FAM20C substrates
  findings: []
- id: file:human/WFS1/WFS1-deep-research-falcon.md
  title: Deep research report on WFS1
  findings: []