id: Q3MUY2
gene_symbol: PIGY
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGY (PIG-Y) is a small (71-residue) two-transmembrane endoplasmic reticulum
  membrane protein that is a required non-catalytic subunit of the glycosylphosphatidylinositol
  N-acetylglucosaminyltransferase (GPI-GnT) complex. This complex catalyses the first, committed
  step of GPI-anchor biosynthesis, transferring N-acetylglucosamine from UDP-GlcNAc onto
  phosphatidylinositol to form GlcNAc-PI. Within the complex, which additionally comprises the
  catalytic subunit PIGA together with PIGC, PIGH, PIGP, PIGQ and DPM2, PIGY interacts directly with
  PIGA and acts as a regulatory accessory subunit rather than as an independent enzyme. Loss of PIGY
  function causes an inherited GPI-deficiency disorder in the hyperphosphatasia with impaired
  intellectual development / epileptic encephalopathy spectrum (HPMRS6), with reduced cell-surface
  display of GPI-anchored proteins.
existing_annotations:
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) assignment that PIGY is part of the GPI-GnT complex.
      This is directly supported by the defining experimental work and by UniProt, which lists PIGY
      as a component of the complex alongside PIGA, PIGC, PIGH, PIGP, PIGQ and DPM2.
    action: ACCEPT
    reason: Correct and core; PIGY is an established structural component of the GPI-GnT complex.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: Here, we report that human GPI-GnT requires another component, termed
        PIG-Y, a 71 amino acid protein with two transmembrane domains.
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: Component of the glycosylphosphatidylinositol-N-
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment that PIGY is involved in GPI anchor biosynthesis.
      As part of the GPI-GnT complex, PIGY participates in the first step of GPI biosynthesis.
    action: ACCEPT
    reason: Correct and core; this is PIGY's central biological role.
    supported_by:
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: participates in the first step of GPI
        biosynthesis
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic (UniProt SubCell keyword mapping) assignment to the ER membrane, consistent
      with the experimentally determined subcellular location of PIGY as a multi-pass ER membrane
      protein.
    action: ACCEPT
    reason: Correct and core; matches experimental IDA and TAS annotations to the same term.
    supported_by:
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16162815
  qualifier: enables
  review:
    summary: IPI protein-protein interaction annotation (IntAct/UniProt) recording binding to PIGA
      (UniProtKB:P37287). The direct PIGY-PIGA interaction is biologically the most important, being
      the interaction through which PIGY regulates GPI-GnT catalytic activity; however the bare
      "protein binding" term is uninformative about function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, bare "protein binding" (GO:0005515) conveys no functional
      information and should not be retained as a core molecular function. The biologically meaningful
      content (direct interaction with the catalytic subunit PIGA, regulating complex activity) is
      captured by the contributes_to GO:0017176 annotation and by the complex membership term. The
      underlying experimental interaction is genuine, so this is over-annotation rather than an
      incorrect annotation.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: PIG-Y appeared to be directly associated with PIG-A, implying that PIG-Y
        is the key molecule that regulates GPI-GnT activity by binding directly to the catalytic
        subunit PIG-A.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IPI protein-protein interaction annotations (IntAct) from the HuRI human binary
      interactome map, recording high-throughput yeast two-hybrid interactions of PIGY with TMEM72
      (UniProtKB:A0PK05) and ERG28 (UniProtKB:Q9UKR5). These are systematic-screen hits without an
      established functional relationship to PIGY's role in GPI-GnT.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" (GO:0005515) is uninformative per curation guidelines, and these
      particular interactors derive from a large-scale binary interactome screen rather than
      GPI-pathway-focused work, with no demonstrated biological significance for PIGY function. Not
      core. The experimental interaction data are retained in IntAct; this is over-annotation for the
      purposes of representing gene function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Electronic (UniPathway vocabulary mapping, UPA00196) assignment to GPI anchor
      biosynthetic process, consistent with PIGY's role in the first step of GPI biosynthesis.
    action: ACCEPT
    reason: Correct and core; redundant with the IBA and IDA annotations to the same BP term.
    supported_by:
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IPI
  original_reference_id: PMID:16162815
  qualifier: part_of
  review:
    summary: ComplexPortal IPI annotation (CPX-6502) placing PIGY as part of the GPI-GnT complex,
      based on the co-precipitation / reconstitution work that identified PIGY as the seventh
      component.
    action: ACCEPT
    reason: Correct and core; experimentally supported complex membership.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: human GPI-GnT requires another component, termed
        PIG-Y
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: located_in
  review:
    summary: Experimental (IDA, ComplexPortal) localisation of PIGY to the ER membrane, where the
      GPI-GnT complex initiates GPI biosynthesis.
    action: ACCEPT
    reason: Correct and core; this is the established site of action of PIGY and the GPI-GnT complex.
    supported_by:
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0017176
    label: phosphatidylinositol N-acetylglucosaminyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: contributes_to
  review:
    summary: Experimental (IDA) annotation with the contributes_to qualifier, capturing that PIGY is
      required for the phosphatidylinositol N-acetylglucosaminyltransferase activity of the GPI-GnT
      complex. PIGY is not itself the catalytic subunit (that is PIGA); it binds directly to PIGA and
      regulates the complex's activity, so contributes_to is the appropriate qualifier.
    action: ACCEPT
    reason: Correct and represents PIGY's core molecular contribution. The contributes_to qualifier
      correctly reflects that PIGY is a required non-catalytic subunit of the enzyme complex rather
      than an independent catalyst.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: PIG-Y is
        the key molecule that regulates GPI-GnT activity by binding directly to the catalytic
        subunit PIG-A
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162730
  qualifier: located_in
  review:
    summary: Traceable author statement (Reactome) localising the GlcNAc-PI-forming reaction and its
      catalysing complex, including PIGY, to the ER membrane.
    action: ACCEPT
    reason: Correct and core; consistent with the experimental IDA and IEA ER membrane annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-162730
      supporting_text: The first step of GPI synthesis is the transfer of N-acetylglucosamine from
        cytosolic UDP-N-acetylglucosamine to phosphatidyl inositol (PI) in the endoplasmic
        reticulum membrane.
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: part_of
  review:
    summary: Experimental (IDA, MGI) annotation placing PIGY as part of the GPI-GnT complex, from the
      study that identified PIGY as the seventh required component of the complex.
    action: ACCEPT
    reason: Correct and core; experimentally established complex membership.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: A complex of six components was formed without PIG-Y.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: located_in
  review:
    summary: Experimental (IDA, MGI) localisation to the plasma membrane. PIGY is an ER-resident
      GPI-GnT subunit; its established site of function is the ER membrane, and UniProt records
      only the ER membrane as its subcellular location. A plasma membrane assignment is inconsistent
      with an ER GPI-biosynthesis subunit and most likely reflects an overexpression/tag-driven
      readout in the original study.
    action: MARK_AS_OVER_ANNOTATED
    reason: The functionally relevant, well-established location of PIGY is the ER membrane (multiple
      IDA/IEA/TAS annotations and UniProt). Plasma membrane localisation does not fit PIGY's role in
      the ER-localised GPI-GnT complex. Because this is an experimental annotation whose full text is
      not available in the cache, it is not removed but flagged as an over-annotation / non-core
      location.
    supported_by:
    - reference_id: file:human/PIGY/PIGY-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: acts_upstream_of_or_within
  review:
    summary: Experimental (IDA, MGI) annotation that PIGY acts upstream of or within GPI anchor
      biosynthesis, based on the demonstration that the PIGY-null Daudi cell line is severely
      defective in surface expression of GPI-anchored proteins.
    action: ACCEPT
    reason: Correct and core; loss of PIGY abolishes GPI-GnT function and hence GPI-anchor
      biosynthesis.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: The Burkitt
        lymphoma cell line Daudi, severely defective in the surface expression of
        GPI-anchored proteins, was a null mutant of PIG-Y.
core_functions:
- description: Required non-catalytic subunit of the GPI-GnT complex that contributes to the
    phosphatidylinositol N-acetylglucosaminyltransferase activity catalysing the first step of GPI
    biosynthesis (GlcNAc transfer from UDP-GlcNAc to phosphatidylinositol), acting by direct binding
    to and regulation of the catalytic subunit PIGA in the ER membrane.
  supported_by:
  - reference_id: PMID:16162815
    supporting_text: PIG-Y is
      the key molecule that regulates GPI-GnT activity by binding directly to the catalytic
      subunit PIG-A
  contributes_to_molecular_function:
    id: GO:0017176
    label: phosphatidylinositol N-acetylglucosaminyltransferase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:16162815
  title: The initial enzyme for glycosylphosphatidylinositol biosynthesis requires
    PIG-Y, a seventh component.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defining paper for PIGY; identifies PIGY as the seventh component of the GPI-GnT
      complex, a 71-aa two-TM ER protein that binds directly to and regulates the catalytic subunit
      PIGA. Abstract-only in cache (full_text_available false); all supporting quotes verified as
      verbatim substrings of the cached abstract.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI large-scale binary (Y2H) interactome map; source of PIGY protein-binding IPI
      annotations to TMEM72 and ERG28. Correctly cited but provides only bare protein-binding data
      with no established functional significance for PIGY; interactors are not GPI-pathway related.
- id: Reactome:R-HSA-162730
  title: phosphatidylinositol + UDP-N-acetyl-D-glucosamine -> N-acetylglucosaminyl-PI
    + UDP
  findings: []
- id: file:human/PIGY/PIGY-uniprot.txt
  title: UniProtKB entry Q3MUY2 (PIGY_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt/Swiss-Prot record; provides curated FUNCTION, SUBUNIT, SUBCELLULAR
      LOCATION, PATHWAY and DISEASE annotations used as supporting text.