id: Q9BRB3
gene_symbol: PIGQ
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PIGQ (also known as GPI1 or PIG-Q) is a non-catalytic subunit of the
  glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
  complex, the multi-protein enzyme that catalyses the first, committed step of
  glycosylphosphatidylinositol (GPI) anchor biosynthesis: transfer of
  N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol to form
  GlcNAc-phosphatidylinositol. Within this complex, PIGA is the catalytic
  subunit, while PIGQ is a required accessory subunit (together with PIGC, PIGH,
  PIGP, PIGY and DPM2) that stabilises the complex and supports its activity;
  PIGQ itself has no independent enzymatic activity. It is a multi-pass integral
  membrane protein of the endoplasmic reticulum membrane, where the GPI-GnT
  complex assembles and acts. Biallelic loss-of-function variants in PIGQ cause
  multiple congenital anomalies-hypotonia-seizures syndrome 4 (MCAHS4), an
  autosomal-recessive inherited GPI-deficiency disorder presenting as a
  developmental and epileptic encephalopathy with refractory neonatal seizures,
  severe global developmental delay, dysmorphism and skeletal, renal and
  ophthalmic anomalies.
alternative_products:
- name: '1'
  id: Q9BRB3-1
- name: '2'
  id: Q9BRB3-2
  sequence_note: VSP_007281, VSP_007282
- name: '3'
  id: Q9BRB3-3
  sequence_note: VSP_007279, VSP_007280
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing PIGQ in the endoplasmic reticulum.
      This is correct: the GPI-GnT complex containing PIGQ was biochemically
      shown to be an ER-membrane complex (PMID:9463366). ER is a core location,
      though the more specific ER membrane term (GO:0005789, below) better
      captures the localization of this multi-pass membrane protein.
    action: ACCEPT
    reason: >-
      Consistent with experimental localization of the GPI-GnT complex to the ER
      membrane and conserved across orthologs.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: >-
        four mammalian gene products form a protein complex in the endoplasmic
        reticulum membrane
- 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) annotation to GPI anchor biosynthetic process. This is
      the core biological process for PIGQ: as a subunit of the GPI-GnT complex
      it participates in the first step of GPI biosynthesis, and the mammalian
      GPI1 protein functionally rescues yeast gpi1 mutants defective in this
      process (PMID:9729469).
    action: ACCEPT
    reason: >-
      Core, well-supported and phylogenetically conserved biological role.
    supported_by:
    - reference_id: PMID:9729469
      supporting_text: >-
        the mammalian GPI1 homologues can rescue haploids
    - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
      supporting_text: participates in the first step of GPI
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation (InterPro IPR007720 PigQ/GPI1 signature plus
      UniPathway) to GPI anchor biosynthetic process. The InterPro-to-GO mapping
      is accurate for this family-defining domain and agrees with the
      experimental and phylogenetic annotations to the same term.
    action: ACCEPT
    reason: >-
      Correct family-level electronic inference, concordant with experimental
      evidence for the same process.
    supported_by:
    - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
      supporting_text: participates in the first step of GPI
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to the generic term membrane (from UniProt SubCell
      SL-0162 / InterPro). PIGQ is indeed a multi-pass membrane protein, but the
      specific compartment is known experimentally to be the endoplasmic
      reticulum membrane (PMID:9463366; PMID:16162815). The generic membrane
      term is uninformative and should be replaced by the more specific ER
      membrane term.
    action: MODIFY
    reason: >-
      Too general; experimental evidence localizes PIGQ/the GPI-GnT complex
      specifically to the ER membrane, so GO:0005789 is the appropriate term.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
      supporting_text: Membrane
    - reference_id: PMID:9463366
      supporting_text: >-
        four mammalian gene products form a protein complex in the endoplasmic
        reticulum membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10944123
  qualifier: enables
  review:
    summary: >-
      IPI (IntAct) annotation recording binary interactions of PIGQ/GPI1 with
      DPM2 and PIGA. These are physiological partners within the GPI-GnT
      complex: DPM2 associates with GPI-GnT through interactions that include
      GPI1, and PIG-P associates with both PIG-A and GPI1 (PMID:10944123). The
      bare "protein binding" term is uninformative; the underlying biology is
      captured by part_of the GPI-GnT complex (GO:0000506).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" (GO:0005515) is too generic to convey function; the
      documented interactions are with fellow GPI-GnT subunits and are better
      represented by complex membership. Retained (not removed) as an
      experimental interaction annotation.
    supported_by:
    - reference_id: PMID:10944123
      supporting_text: >-
        DPM2, but not two other components of dolichol-phosphate-mannose
        synthase, associates with GPI-GnT through interactions with PIG-A, PIG-C
        and GPI1
    - reference_id: PMID:10944123
      supporting_text: >-
        PIG-P, a 134-amino acid protein having two hydrophobic domains,
        associates with PIG-A and GPI1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16162815
  qualifier: enables
  review:
    summary: >-
      IPI (IntAct) annotation recording interaction of PIGQ with PIGA, a
      co-subunit of the GPI-GnT complex characterized in this study
      (PMID:16162815). As above, "protein binding" is uninformative and the
      interaction reflects assembly of the GPI-GnT complex (GO:0000506).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic MF term; the interaction is with a fellow complex subunit and is
      better captured by GPI-GnT complex membership. Retained as an experimental
      interaction annotation.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: >-
        Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an
        unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT)
        consisting of at least six proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI (IntAct) annotation from the BioPlex 3.0 proteome-scale AP-MS
      interactome (PMID:33961781), recording interaction of PIGQ with PIGH, a
      GPI-GnT subunit. High-throughput; "protein binding" is uninformative and
      the interaction is consistent with GPI-GnT complex membership
      (GO:0000506).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic MF term from a high-throughput interactome screen; the partner is
      a fellow complex subunit, better represented by complex membership.
      Retained as an experimental interaction annotation.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        BioPlex 3.0, results from affinity purification of 10,128 human
        proteins-half the proteome-in 293T cells and includes 118,162
        interactions among 14,586 proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      IPI (IntAct) annotation from a multimodal cell-map AP-MS study
      (PMID:40205054), recording interaction of PIGQ with PIGH. As with the
      other IPI annotations, "protein binding" is uninformative; the partner is
      a GPI-GnT subunit, consistent with complex membership (GO:0000506).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic MF term from a high-throughput interactome/imaging study; the
      partner is a fellow complex subunit. Retained as an experimental
      interaction annotation.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: >-
        a total of 36,842 interactions among 7,543 proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9463366
  qualifier: enables
  review:
    summary: >-
      IPI (IntAct) annotation recording interactions of PIGQ/GPI1 with PIGA,
      PIGC and PIGH. This is the foundational study defining the
      PIG-A/PIG-H/PIG-C/GPI1 complex in the ER membrane (PMID:9463366). The bare
      "protein binding" term is uninformative; the biology is captured by
      GPI-GnT complex membership (GO:0000506).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic MF term; all partners are fellow GPI-GnT subunits and the
      interactions define the complex, which is better represented by GO:0000506.
      Retained as an experimental interaction annotation.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: >-
        four mammalian gene products form a protein complex in the endoplasmic
        reticulum membrane
- term:
    id: GO:0000506
    label: glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT)
      complex
  evidence_type: IPI
  original_reference_id: PMID:16162815
  qualifier: part_of
  review:
    summary: >-
      PIGQ is a component of the GPI-GnT complex. This ComplexPortal annotation
      (CPX-6502) records PIGQ as a subunit of the seven-component GPI-GnT complex
      (PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, DPM2) characterized in PMID:16162815.
      This is a core cellular-component annotation for PIGQ.
    action: ACCEPT
    reason: >-
      Directly supported by biochemical characterization of the GPI-GnT complex;
      PIGQ is an established subunit.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: >-
        Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an
        unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT)
        consisting of at least six proteins
    - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
      supporting_text: PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: located_in
  review:
    summary: >-
      IDA annotation localizing PIGQ to the endoplasmic reticulum membrane,
      where the GPI-GnT complex assembles and acts. The GPI-GnT complex was
      biochemically shown to reside in the ER membrane (PMID:9463366), and PIGQ
      is a multi-pass ER-membrane protein. Core location.
    action: ACCEPT
    reason: >-
      Specific, experimentally supported subcellular localization consistent
      with the complex's site of action.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: >-
        four mammalian gene products form a protein complex 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: >-
      IDA annotation (UniProt) recording PIGQ as part of the GPI-GnT complex,
      based on the biochemical characterization in PMID:16162815. Duplicate of
      the ComplexPortal complex annotation with direct experimental evidence;
      core cellular-component annotation.
    action: ACCEPT
    reason: >-
      Directly supported by experimental characterization of the GPI-GnT
      complex; PIGQ is an established subunit.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: >-
        A complex of six components was formed without PIG-Y
    - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
      supporting_text: PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16162815
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation to GPI anchor biosynthetic process, from the study
      establishing the seven-component GPI-GnT complex that catalyses the first
      step of GPI biosynthesis (PMID:16162815). This is the core biological
      process for PIGQ.
    action: ACCEPT
    reason: >-
      Core process, directly supported by characterization of the GPI-GnT
      complex to which PIGQ belongs.
    supported_by:
    - reference_id: PMID:16162815
      supporting_text: >-
        Biosynthesis of glycosylphosphatidylinositol (GPI) is initiated by an
        unusually complex GPI-N-acetylglucosaminyltransferase (GPI-GnT)
        consisting of at least six proteins
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162730
  qualifier: located_in
  review:
    summary: >-
      TAS annotation from Reactome localizing the GlcNAc-PI-forming reaction and
      its catalysing multimeric enzyme to the ER membrane. Concordant with the
      IDA ER-membrane annotation; core location.
    action: ACCEPT
    reason: >-
      Consistent with experimental localization of the GPI-GnT complex to the ER
      membrane.
    supported_by:
    - reference_id: PMID:9463366
      supporting_text: >-
        four mammalian gene products form a protein complex in the endoplasmic
        reticulum membrane
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: TAS
  original_reference_id: PMID:9729469
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to the very broad term carbohydrate metabolic process,
      based on the cloning/functional-complementation study of GPI1
      (PMID:9729469). While technically true (the GPI-GnT reaction transfers a
      sugar), this term is far too general. The specific process is GPI anchor
      biosynthesis (formation of GlcNAc-PI), already captured by GO:0006506.
    action: MODIFY
    reason: >-
      Overly general; the informative and accurate term is GPI anchor
      biosynthetic process (GO:0006506), which describes the actual pathway PIGQ
      participates in.
    proposed_replacement_terms:
    - id: GO:0006506
      label: GPI anchor biosynthetic process
    supported_by:
    - reference_id: PMID:9729469
      supporting_text: >-
        allow conclusions about a specific function for Gpi1p in stabilizing the
        enzymic complex
core_functions:
- description: >-
    Non-catalytic subunit of the GPI-N-acetylglucosaminyltransferase (GPI-GnT)
    complex, contributing to the first committed step of GPI-anchor biosynthesis
    (transfer of GlcNAc from UDP-GlcNAc to phosphatidylinositol) at the ER
    membrane; PIGQ stabilises the complex rather than performing catalysis
    itself (the catalytic subunit is PIGA).
  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
  supported_by:
  - reference_id: PMID:9463366
    supporting_text: >-
      four mammalian gene products form a protein complex in the endoplasmic
      reticulum membrane
  - reference_id: PMID:9729469
    supporting_text: >-
      allow conclusions about a specific function for Gpi1p in stabilizing the
      enzymic complex
  - reference_id: file:human/PIGQ/PIGQ-uniprot.txt
    supporting_text: participates in the first step of GPI
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the precise structural and mechanistic contribution of PIGQ within
    the GPI-GnT complex - does it act purely as a scaffolding/stabilising
    subunit, or does it also modulate substrate (phosphatidylinositol) selection
    or catalytic rate?
suggested_experiments:
- description: >-
    Reconstitute the human GPI-GnT complex with and without PIGQ and measure
    GlcNAc-PI transferase activity and complex stability to quantify PIGQ's
    contribution to assembly versus catalysis.
- description: >-
    Determine a cryo-EM structure of the intact human GPI-GnT complex to define
    PIGQ's interfaces with PIGA (catalytic subunit), PIGC, PIGH, PIGP, PIGY and
    DPM2.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10944123
  title: Initial enzyme for glycosylphosphatidylinositol biosynthesis requires PIG-P
    and is regulated by DPM2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes GPI1/PIGQ as a component of the GPI-GnT complex and its
      interactions with PIG-P and DPM2 within the complex. Supports IPI and
      complex-membership annotations.
- 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: >-
      Defines the seven-component GPI-GnT complex including PIGQ; source of the
      IDA GPI-GnT-complex, ER-membrane and GPI-anchor-biosynthesis annotations.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput BioPlex 3.0 AP-MS interactome; contributes a PIGQ-PIGH
      interaction underpinning a generic protein-binding annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput multimodal (AP-MS + imaging) cell-map study; contributes a
      PIGQ-PIGH interaction underpinning a generic protein-binding annotation.
- id: PMID:9463366
  title: The first step of glycosylphosphatidylinositol biosynthesis is mediated by
    a complex of PIG-A, PIG-H, PIG-C and GPI1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Foundational study cloning human GPI1 and defining the PIG-A/PIG-H/PIG-C/GPI1
      complex in the ER membrane with GPI-GnT activity in vitro.
- id: PMID:9729469
  title: Human and mouse Gpi1p homologues restore glycosylphosphatidylinositol membrane
    anchor biosynthesis in yeast mutants.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows mammalian GPI1 functionally complements yeast gpi1 mutants and
      concludes GPI1's role is stabilising the GPI-GnT enzymic complex.
- id: Reactome:R-HSA-162730
  title: phosphatidylinositol + UDP-N-acetyl-D-glucosamine -> N-acetylglucosaminyl-PI
    + UDP
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the first step of GPI biosynthesis, localized to the
      ER membrane; supports the TAS ER-membrane annotation.
- id: file:human/PIGQ/PIGQ-uniprot.txt
  title: UniProtKB entry Q9BRB3 (PIGQ_HUMAN)
  findings: []