id: Q9H490
gene_symbol: PIGU
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PIGU (GPI-anchor transamidase component PIG-U; also called CDC91L1) is a multi-pass
  endoplasmic reticulum membrane protein that is one of the five subunits of the
  glycosylphosphatidylinositol (GPI) transamidase (GPI-T) complex, together with the
  catalytic subunit PIGK and the accessory subunits GPAA1, PIGT and PIGS. GPI-T acts in
  the ER lumen to remove the C-terminal GPI-attachment signal peptide from proprotein
  substrates and covalently attach a pre-assembled GPI anchor at the newly exposed
  C-terminus (the omega-site), thereby generating mature GPI-anchored proteins. PIGU is a
  non-catalytic, accessory subunit: it binds the lipid portion of the GPI substrate and is
  thought to help recognise and present the lipid GPI, and to organise the transmembrane
  layer of the complex by recruiting the other subunits; cells lacking PIGU still assemble
  the remaining four subunits but have no transamidase activity. Biallelic loss-of-function
  variants in PIGU cause an inherited GPI-anchor deficiency (a GPI biosynthesis deficiency,
  GPIBD), a neurodevelopmental disorder with developmental delay, intellectual disability,
  epilepsy and brain anomalies.
alternative_products:
- name: '1'
  id: Q9H490-1
- name: '2'
  id: Q9H490-2
  sequence_note: VSP_009543
existing_annotations:
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically-inferred annotation that PIGU participates in attachment of the GPI
      anchor to protein. This is the core biological process of PIGU as a subunit of the
      GPI transamidase complex, well supported by experimental and structural work.
    action: ACCEPT
    reason: >-
      PIGU is an essential subunit of the ER GPI transamidase complex, whose function is to
      attach pre-assembled GPI anchors to the C-terminus of proprotein substrates. The IBA
      is at the correct level of specificity for this shared ancestral function.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        Attachment of GPI to proteins is mediated by the GPI-transamidase (GPI-TA) complex,
        which recognizes and cleaves the C-terminal GPI attachment signal of precursor
        proteins
    - reference_id: PMID:12802054
      supporting_text: >-
        posttranslationally attached to the carboxyl-terminus by GPI transamidase
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      Phylogenetically-inferred annotation that PIGU is part of the GPI-anchor transamidase
      complex. This is the core cellular-component annotation for PIGU.
    action: ACCEPT
    reason: >-
      PIGU is one of the five conserved subunits of the GPI transamidase complex (PIGK,
      GPAA1, PIGT, PIGS, PIGU), confirmed biochemically and by cryo-EM structures.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and the absence
        of any subunit leads to the loss of activity
    - reference_id: PMID:35165458
      supporting_text: >-
        The GPIT complex is known to be composed of five subunits: PIGK, PIGU, PIGT, PIGS
        and GPAA1
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation (UniProt Subcellular Location mapping) placing PIGU in the ER
      membrane. This matches the experimentally established localization of GPI-T.
    action: ACCEPT
    reason: >-
      PIGU is a multi-pass ER membrane protein; GPI anchoring occurs in the ER. The IEA
      subcellular-location mapping is correct and specific.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the generic parent term membrane. Correct but
      uninformative given the specific ER membrane annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      PIGU is an integral membrane protein, so membrane is not wrong, but it is a broad
      parent of the more specific and better-supported endoplasmic reticulum membrane
      (GO:0005789) annotation. Retain as non-core.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation (IPR009600, PIG-U) that PIGU is involved in
      attachment of the GPI anchor to protein. Consistent with the core function.
    action: ACCEPT
    reason: >-
      The InterPro PIG-U signature maps to the correct core biological process; this is the
      same well-supported function inferred by IBA and demonstrated experimentally.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        Attachment of GPI to proteins is mediated by the GPI-transamidase (GPI-TA) complex,
        which recognizes and cleaves the C-terminal GPI attachment signal of precursor
        proteins
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro2GO electronic annotation that PIGU is part of the GPI-anchor transamidase
      complex, consistent with experimental evidence.
    action: ACCEPT
    reason: >-
      The InterPro PIG-U signature correctly maps PIGU to its complex; supported by
      biochemistry and cryo-EM structures.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        The GPIT complex is known to be composed of five subunits: PIGK, PIGU, PIGT, PIGS
        and GPAA1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IntAct annotation of a binary interaction (PIGU with KASH5/Q8N6L0) captured in the
      HuRI high-throughput yeast two-hybrid interactome map. protein binding is an
      uninformative molecular-function term and this specific interaction is not part of
      PIGU's established function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The generic protein binding term conveys no specific molecular function, and the
      single high-throughput Y2H interaction with KASH5 has no established role in GPI
      transamidase biology. Per curation policy this bare protein-binding IPI is marked as
      over-annotated rather than removed. PIGU's informative binding activity (GPI anchor
      binding) is captured by a separate annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        With approximately 53,000 protein-protein interactions, HuRI has approximately four
        times as many such interactions as there are high-quality curated interactions from
        small-scale studies
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-based electronic annotation (Ensembl Compara, from rat Pigu) that PIGU is
      involved in GPI anchored protein biosynthesis. Consistent with the core function.
    action: ACCEPT
    reason: >-
      GPI anchored protein biosynthesis is the pathway that GPI-T (and therefore PIGU)
      participates in; the orthology transfer is appropriate.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        Attachment of GPI to proteins is mediated by the GPI-transamidase (GPI-TA) complex,
        which recognizes and cleaves the C-terminal GPI attachment signal of precursor
        proteins
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation (UPA00196) to GPI anchor biosynthetic process.
      This is the pathway to which PIGU/GPI-T contributes.
    action: ACCEPT
    reason: >-
      The GPI transamidase step is part of GPI-anchor biosynthesis; the UniPathway mapping
      is correct.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        a transmembrane complex composed of five subunits: GAAP1 (Gaa1p), PIGK (Gpi8p),
        PIGS (Gpi17p), PIGT (Gpi16p), and PIGU (Gab1p)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal NAS annotation placing PIGU in the ER membrane, consistent with the
      established ER localization of GPI-T.
    action: ACCEPT
    reason: >-
      GPI anchoring occurs on the ER membrane and PIGU is a multi-pass ER membrane subunit;
      the ER membrane location is well established.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: >-
        The GPI transamidase mediates GPI anchoring in the endoplasmic reticulum
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: NAS
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS annotation that PIGU is involved in attachment of the GPI anchor to
      protein, the core process for the GPI transamidase complex.
    action: ACCEPT
    reason: >-
      Hong et al. established PIGU (PIG-U) as the fifth subunit of GPI transamidase, which
      attaches GPI anchors to proteins; this is the core function.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        PIG-U and the yeast orthologue Cdc91p are the fifth component of GPI transamidase
        that may be involved in the recognition of either the GPI attachment signal or the
        lipid portion of GPI
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IPI
  original_reference_id: PMID:12802054
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal IPI annotation that PIGU is part of the GPI-anchor transamidase complex,
      based on affinity purification of the complex containing PIG-U.
    action: ACCEPT
    reason: >-
      The GPI transamidase complex affinity-purified from cells contained PIG-U together
      with the four other known components, directly demonstrating complex membership.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        The GPI transamidase complex affinity-purified from cells expressing
        epitope-tagged-GPI8 contained PIG-U and four other known components
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation (cryo-EM structure of the human GPI transamidase) that PIGU is
      involved in GPI anchored protein biosynthesis.
    action: ACCEPT
    reason: >-
      The structural study resolved PIGU as one of the five subunits of the ER GPI
      transamidase that is essential for maturation of GPI-anchored proteins.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        Attaching GPI to the protein in the endoplasmic reticulum (ER) is catalyzed by the
        transmembrane GPI transamidase (GPIT) complex
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation (cryo-EM of the equimolar heteropentameric human GPI-T) that
      PIGU is involved in GPI anchored protein biosynthesis.
    action: ACCEPT
    reason: >-
      The structure of the five-subunit ER GPI-T, including PIGU, supports its role in the
      biosynthesis of GPI-anchored proteins.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0034235
    label: GPI anchor binding
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: enables
  review:
    summary: >-
      Direct-assay annotation that PIGU binds the GPI anchor. The liganded GPI-T structures
      show that PIGU contacts the GPI substrate, and UniProt records that PIGU binds the
      lipid portion of the GPI-anchor. This is the informative subunit-level molecular
      function of PIGU (distinct from the complex-level transamidase catalysis, which is
      performed by PIGK).
    action: ACCEPT
    reason: >-
      PIGU is the subunit thought to recognise and present the lipid GPI substrate; it binds
      the lipid portion of the GPI-anchor. GPI anchor binding is an informative
      molecular-function term consistent with the structural data and PIGU's homology to
      lipid-handling GPI biosynthetic enzymes.
    supported_by:
    - reference_id: file:human/PIGU/PIGU-uniprot.txt
      supporting_text: >-
        Binds the lipid portion of GPI-anchor (PubMed:37684232). May act as an
    - reference_id: PMID:34576938
      supporting_text: >-
        PIGU is homologous with other GPI biosynthetic enzymes (such as PIGW and PIGM),
        suggesting that it recognizes the lipid portion of GPI
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation that PIGU is involved in attachment of the GPI anchor to
      protein. Class U (PIGU-deficient) cells lack GPI transamidase activity and cannot
      cleave the GPI attachment signal peptide.
    action: ACCEPT
    reason: >-
      Loss of PIGU abolishes GPI transamidase activity in cells, directly demonstrating that
      PIGU is required for attachment of the GPI anchor to protein.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        The class U cells accumulated mature and immature GPI and did not have in vitro GPI
        transamidase activity
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:31353022
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation from the disease study that PIGU is involved in attachment of
      the GPI anchor to protein; PIGU is described as an essential component of the GPI
      transamidase complex, and pathogenic variants impair GPI-anchored protein surface
      expression.
    action: ACCEPT
    reason: >-
      Functional characterization of NEDBSS variants showed reduced GPI-anchored protein
      expression, confirming PIGU's essential role in GPI anchor attachment.
    supported_by:
    - reference_id: PMID:31353022
      supporting_text: >-
        An essential component of the GPI transamidase complex is PIGU, along with PIGK,
        PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI
        anchor in the endoplasmic reticulum (ER)
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation that PIGU is involved in attachment of the GPI anchor to
      protein; mutagenesis of PIGU residues (Leu375/Trp376) reduced GPI-TA rescue activity,
      and loss of PIGU abolishes activity of the complex.
    action: ACCEPT
    reason: >-
      Functional analysis of GPI-TA subunits demonstrated that PIGU is required for
      transamidase activity and identified functionally important PIGU residues.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        Lacking PIGU, other subunits (PIGK, GPAA1, PIGT and PIGS) still form a complex, but
        have no activity
- term:
    id: GO:0180046
    label: GPI anchored protein biosynthesis
  evidence_type: IDA
  original_reference_id: PMID:31353022
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation from the disease study that PIGU is involved in GPI anchored
      protein biosynthesis; variant cells show reduced surface GPI-anchored proteins.
    action: ACCEPT
    reason: >-
      PIGU is required for biosynthesis/surface expression of GPI-anchored proteins, and
      biallelic PIGU variants cause an inherited GPI-anchor deficiency.
    supported_by:
    - reference_id: PMID:31353022
      supporting_text: >-
        An essential component of the GPI transamidase complex is PIGU, along with PIGK,
        PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI
        anchor in the endoplasmic reticulum (ER)
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation (liganded GPI-T structures) that PIGU is involved in
      attachment of the GPI anchor to protein, as a subunit of the transmembrane complex
      that adds GPI to proproteins.
    action: ACCEPT
    reason: >-
      The substrate- and product-bound GPI-T structures include PIGU as one of the five
      subunits that together carry out the transamidation reaction.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        a transmembrane complex composed of five subunits: GAAP1 (Gaa1p), PIGK (Gpi8p),
        PIGS (Gpi17p), PIGT (Gpi16p), and PIGU (Gab1p)
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:37684232
  qualifier: part_of
  review:
    summary: >-
      Direct-assay annotation (cryo-EM) that PIGU is part of the GPI-anchor transamidase
      complex.
    action: ACCEPT
    reason: >-
      The liganded GPI-T structures resolve PIGU as an integral subunit of the five-subunit
      complex.
    supported_by:
    - reference_id: PMID:37684232
      supporting_text: >-
        a transmembrane complex composed of five subunits: GAAP1 (Gaa1p), PIGK (Gpi8p),
        PIGS (Gpi17p), PIGT (Gpi16p), and PIGU (Gab1p)
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation (cryo-EM structure) that PIGU is involved in attachment of the
      GPI anchor to protein.
    action: ACCEPT
    reason: >-
      The human GPI-T structure, including PIGU, defines the transmembrane GPI
      substrate-binding cleft and supports the complex's role in attaching GPI to proteins.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        Transmembrane helices constitute a widely opened cleft, which is located underneath
        PIGK, serving as a GPI substrate-binding site
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay annotation (cryo-EM structure) that PIGU is involved in attachment of the
      GPI anchor to protein, as a subunit of the ER GPI transamidase.
    action: ACCEPT
    reason: >-
      The equimolar heteropentameric GPI-T structure, including PIGU, supports its role in
      attaching GPI anchors to proproteins in the ER.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:35165458
  qualifier: part_of
  review:
    summary: >-
      Direct-assay annotation (cryo-EM) that PIGU is part of the GPI-anchor transamidase
      complex.
    action: ACCEPT
    reason: >-
      The human GPI-T structure directly resolves PIGU as one of the five subunits of the
      complex.
    supported_by:
    - reference_id: PMID:35165458
      supporting_text: >-
        The GPIT complex is known to be composed of five subunits: PIGK, PIGU, PIGT, PIGS
        and GPAA1
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:35551457
  qualifier: part_of
  review:
    summary: >-
      Direct-assay annotation (cryo-EM) that PIGU is part of the GPI-anchor transamidase
      complex, an equimolar heteropentamer.
    action: ACCEPT
    reason: >-
      The structure reveals an equimolar heteropentameric assembly that includes PIGU.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        revealing an equimolar heteropentameric assembly
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:34576938
  qualifier: part_of
  review:
    summary: >-
      Direct-assay annotation that PIGU is part of the GPI-anchor transamidase complex,
      which was purified with all five subunits including PIGU.
    action: ACCEPT
    reason: >-
      GPI-TA consists of five subunits including PIGU, and the purified complex contained
      all five; PIGU is a bona fide member.
    supported_by:
    - reference_id: PMID:34576938
      supporting_text: >-
        GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and the absence
        of any subunit leads to the loss of activity
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (membrane proteome of an NK-like cell line) detected PIGU in
      the membrane fraction. Correct but non-specific relative to the ER membrane annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with PIGU being an integral membrane protein, but membrane is a broad parent
      term; the specific ER membrane location is better supported. Retain as non-core.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        Mass spectrometric analysis identified 1843 proteins with high confidence scores
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162836
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement annotation placing PIGU in the ER membrane in the
      context of the GPI-anchor attachment reaction. Consistent with the established
      localization.
    action: ACCEPT
    reason: >-
      GPI anchoring occurs on the ER membrane; the Reactome pathway correctly localizes PIGU
      there.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: IMP
  original_reference_id: PMID:12802054
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype annotation: PIGU-deficient (class U) cells cannot attach GPI anchors to
      proteins and lack transamidase activity, demonstrating PIGU's requirement in this
      process.
    action: ACCEPT
    reason: >-
      Class U cells accumulate GPI and lack GPI transamidase activity, and cannot cleave the
      GPI attachment signal peptide, directly implicating PIGU in GPI anchor attachment.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        The class U cells accumulated mature and immature GPI and did not have in vitro GPI
        transamidase activity
- term:
    id: GO:0034235
    label: GPI anchor binding
  evidence_type: IMP
  original_reference_id: PMID:12802054
  qualifier: contributes_to
  review:
    summary: >-
      Mutant-phenotype annotation (contributes_to) that PIGU contributes to GPI anchor
      binding within the transamidase complex. Hong et al. proposed that PIG-U/Cdc91p is
      involved in recognition of the lipid portion of GPI.
    action: ACCEPT
    reason: >-
      The contributes_to qualifier is appropriate for an accessory subunit: PIGU is proposed
      to recognise the lipid portion of the GPI substrate as part of the complex, consistent
      with later structural evidence that PIGU binds the lipid portion of the GPI-anchor.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        PIG-U and the yeast orthologue Cdc91p are the fifth component of GPI transamidase
        that may be involved in the recognition of either the GPI attachment signal or the
        lipid portion of GPI
- term:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  evidence_type: IDA
  original_reference_id: PMID:12802054
  qualifier: part_of
  review:
    summary: >-
      Direct-assay annotation that PIGU is part of the GPI-anchor transamidase complex,
      based on affinity purification of the complex containing PIG-U and four other
      components.
    action: ACCEPT
    reason: >-
      The affinity-purified GPI transamidase complex contained PIG-U together with the four
      other known subunits, directly demonstrating complex membership.
    supported_by:
    - reference_id: PMID:12802054
      supporting_text: >-
        The GPI transamidase complex affinity-purified from cells expressing
        epitope-tagged-GPI8 contained PIG-U and four other known components
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15034568
  qualifier: located_in
  review:
    summary: >-
      Annotation to plasma membrane from the bladder-cancer oncogene study of overexpressed
      CDC91L1 (PIG-U). PIGU is an ER-resident, multi-pass ER membrane protein; its
      established site of action is the ER membrane, not the plasma membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Later biochemical and structural work firmly localizes PIGU/GPI-T to the ER membrane,
      where GPI anchoring occurs; the plasma membrane localization does not represent PIGU's
      core function and likely reflects the overexpression/oncogene context. Per curation
      policy this experimental annotation is marked as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:35551457
      supporting_text: >-
        an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among
        all eukaryotes
    - reference_id: PMID:15034568
      supporting_text: >-
        a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring
        pathway
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15034568
  qualifier: involved_in
  review:
    summary: >-
      Annotation that PIGU is involved in GPI anchor biosynthetic process, from the
      bladder-cancer study describing PIG-U as a transamidase-complex unit in the GPI
      anchoring pathway. Consistent with PIGU's core role.
    action: ACCEPT
    reason: >-
      PIG-U is described as a transamidase-complex unit in the GPI anchoring pathway; this is
      the correct, core biosynthetic process, corroborated by all subsequent work.
    supported_by:
    - reference_id: PMID:15034568
      supporting_text: >-
        a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring
        pathway
- term:
    id: GO:0046425
    label: regulation of receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:15034568
  qualifier: involved_in
  review:
    summary: >-
      Annotation derived from the bladder-cancer study, where PIG-U overexpression upregulated
      the GPI-anchored urokinase receptor (uPAR) and increased STAT-3 phosphorylation. This is
      a downstream, indirect consequence of aberrant PIGU overexpression, not a core direct
      molecular activity of PIGU.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      PIGU has no direct role in JAK-STAT signaling; the observed STAT-3 phosphorylation is an
      indirect effect of increased surface uPAR (a GPI-anchored protein) upon PIG-U
      overexpression in cancer cells. This reflects a pathological overexpression phenotype
      rather than PIGU's normal function, so it is marked as over-annotated (kept, not
      removed, per policy for experimental annotations).
    supported_by:
    - reference_id: PMID:15034568
      supporting_text: >-
        Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor
        (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in
        bladder cancer cells
- term:
    id: GO:0016255
    label: attachment of GPI anchor to protein
  evidence_type: TAS
  original_reference_id: PMID:11483512
  qualifier: involved_in
  review:
    summary: >-
      Traceable-author-statement annotation that PIGU is involved in attachment of the GPI
      anchor to protein. This paper describes the GPI transamidase complex (GAA1, GPI8,
      PIG-S, PIG-T) that mediates GPI anchoring in the ER; PIGU was later identified as the
      fifth subunit.
    action: ACCEPT
    reason: >-
      The GPI transamidase attaches GPI anchors to proteins in the ER by replacing the
      C-terminal GPI attachment signal peptide with a pre-assembled GPI; PIGU is an essential
      subunit of this complex. The core process is correct.
    supported_by:
    - reference_id: PMID:11483512
      supporting_text: >-
        The GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by
        replacing a protein's C-terminal GPI attachment signal peptide with a pre-assembled
        GPI
core_functions:
- description: >-
    As a non-catalytic accessory subunit of the ER GPI transamidase (GPI-T) complex, PIGU
    binds the lipid portion of the GPI substrate and contributes to attachment of the
    pre-assembled GPI anchor to the C-terminus of proprotein substrates, generating mature
    GPI-anchored proteins.
  molecular_function:
    id: GO:0034235
    label: GPI anchor binding
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  - id: GO:0016255
    label: attachment of GPI anchor to protein
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0042765
    label: GPI-anchor transamidase complex
  supported_by:
  - reference_id: PMID:34576938
    supporting_text: >-
      GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and the absence of
      any subunit leads to the loss of activity
  - reference_id: PMID:34576938
    supporting_text: >-
      PIGU is homologous with other GPI biosynthetic enzymes (such as PIGW and PIGM),
      suggesting that it recognizes the lipid portion of GPI
  - reference_id: file:human/PIGU/PIGU-uniprot.txt
    supporting_text: >-
      Binds the lipid portion of GPI-anchor (PubMed:37684232). May act as an
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- 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: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:11483512
  title: PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a
    complex with GAA1 and GPI8.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes the GPI transamidase complex (GAA1, GPI8/PIGK, PIG-S,
      PIG-T) and that it mediates GPI anchoring in the ER by replacing the C-terminal GPI
      attachment signal peptide; PIGU was identified later as the fifth subunit. Supports the
      pathway/localization framing but does not itself assay PIGU.
- id: PMID:12802054
  title: Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that
    attaches GPI-anchors to proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Primary paper identifying PIGU (PIG-U) as the fifth subunit of GPI
      transamidase; class-U cells lack transamidase activity and cannot cleave the GPI
      attachment signal; proposes PIGU recognises the GPI attachment signal or the lipid
      portion of GPI.
- id: PMID:15034568
  title: CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Correctly identifies PIG-U as a GPI transamidase-complex unit and
      supports its role in the GPI anchoring pathway. The plasma-membrane and JAK-STAT
      annotations derived from this overexpression/oncogene study are downstream/indirect
      effects (uPAR upregulation, STAT-3 phosphorylation), not PIGU's core ER function.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. High-throughput membrane proteomics of an NK-like cell line; supports
      only the generic membrane localization of PIGU.
- id: PMID:31353022
  title: Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing
    Severe Intellectual Disability, Epilepsy, and Brain Anomalies.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes PIGU as an essential GPI transamidase subunit and links
      biallelic PIGU variants to an inherited GPI-anchor deficiency (NEDBSS/GPIBD) with
      intellectual disability, epilepsy and brain anomalies; variant cells show reduced
      surface GPI-anchored proteins.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. HuRI high-throughput Y2H interactome map; source of the single
      PIGU-KASH5 binary interaction underlying the generic protein binding IPI. Not
      informative for PIGU's specific molecular function.
- id: PMID:34576938
  title: Functional Analysis of the GPI Transamidase Complex by Screening for Amino
    Acid Mutations in Each Subunit.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; full text available. Confirms PIGU is one of five GPI-TA subunits,
      that loss of PIGU abolishes complex activity, that PIGU is homologous to lipid-handling
      GPI biosynthetic enzymes (recognises the lipid portion of GPI), and identifies
      functionally important PIGU residues (Leu375/Trp376).
- id: PMID:35165458
  title: Structure of human glycosylphosphatidylinositol transamidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Cryo-EM structure of the five-subunit human GPI-T (including PIGU);
      identifies the PIGK catalytic triad and the transmembrane GPI substrate-binding cleft.
- id: PMID:35551457
  title: Molecular insights into biogenesis of glycosylphosphatidylinositol anchor
    proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Cryo-EM structure of the equimolar heteropentameric human GPI-T (ER
      membrane), including PIGU; defines a composite cavity for the lipid substrate.
- id: PMID:37684232
  title: Structures of liganded glycosylphosphatidylinositol transamidase illuminate
    GPI-AP biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; full text available. Substrate/product-bound GPI-T structures showing
      PIGU as one of five subunits contacting GPI; basis for the UniProt statement that PIGU
      binds the lipid portion of the GPI-anchor.
- id: Reactome:R-HSA-162836
  title: uPAR precursor + acyl-GPI -> uPAR-acyl-GPI + uPAR propeptide
  findings: []
- id: file:human/PIGU/PIGU-uniprot.txt
  title: UniProtKB entry PIGU_HUMAN (Q9H490)
  findings: []