PIGX

id: Q8TBF5
gene_symbol: PIGX
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGX (phosphatidylinositol-glycan biosynthesis class X protein) is the
  non-catalytic stabilizing subunit of GPI mannosyltransferase I (GPI-MT-I), the endoplasmic
  reticulum complex that adds the first mannose during glycosylphosphatidylinositol
  (GPI) anchor biosynthesis. GPI-MT-I transfers this mannose in an alpha-1,4 linkage
  from dolichyl-phosphate-mannose (Dol-P-Man) onto the glucosaminyl-(acyl)phosphatidylinositol
  (GlcN-(acyl)PI) intermediate; PIGX itself has no catalytic activity and instead binds
  and stabilizes the catalytic mannosyltransferase PIGM, protecting it from degradation,
  so that PIGX is required for GPI-MT-I activity. PIGX is a single-pass type I endoplasmic
  reticulum membrane protein and functions as part of the GPI-MT-I complex on the lumenal
  side of the ER membrane. Loss of PIGX/GPI-MT-I function causes inherited GPI deficiency
  (GPI biosynthesis defect), a developmental and epileptic encephalopathy.
alternative_products:
- name: '1'
  id: Q8TBF5-1
- name: '2'
  id: Q8TBF5-2
  sequence_note: VSP_019842
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation (InterPro PIG-X/PBN1 signature plus UniProt Subcellular
      Location mapping) placing PIGX in the ER membrane. This is correct; PIGX is a
      single-pass type I ER membrane protein and GPI biosynthesis occurs on the ER
      membrane, so this is the core localization.
    action: ACCEPT
    reason: Correct localization, consistent with the UniProt-annotated single-pass
      ER membrane topology and with the ComplexPortal, ISS, and Reactome ER-membrane
      annotations.
    supported_by:
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: Single-pass type I membrane protein
- 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 PIG-X signatures and UniPathway GPI-anchor
      biosynthesis) to the GPI anchor biosynthetic process. PIGX is a required subunit
      of GPI-MT-I, which performs the first-mannose-addition step of GPI biosynthesis,
      so this is the core biological process for the gene.
    action: ACCEPT
    reason: Correct and central biological process; PIGX is essential for GPI-MT-I
      activity, which catalyzes step 6 (first mannose) of GPI-anchor biosynthesis.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM functions in association with PIGX, which stabilizes PIGM
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: participates in
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: located_in
  review:
    summary: ComplexPortal (CPX-2697) traceable assertion that PIGX localizes to the
      ER membrane, where GPI is assembled. Consistent with the electronic, ISS, and
      Reactome ER-membrane annotations and with the UniProt single-pass ER topology.
    action: ACCEPT
    reason: Correct localization; the GPI-MT-I complex acts on the lumenal side of
      the ER membrane and PIGX is an ER membrane protein.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER) membrane
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: part_of
  review:
    summary: ComplexPortal (CPX-2697) assertion that PIGX is part of the GPI-mannosyltransferase
      I complex, which in mammals comprises the catalytic subunit PIGM and the stabilizing
      subunit PIGX. This is the defining, characteristic complex membership for PIGX
      and captures how the gene product acts.
    action: ACCEPT
    reason: Well-established complex membership; PIGX is the stabilizing subunit of
      GPI-MT-I and binds/stabilizes catalytic PIGM.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM functions in association with PIGX, which stabilizes PIGM
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: complex that is composed of PIGM and PIGX. Interacts with PIGM;
        PIGX
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer (from mouse Pigx, UniProtKB:Q60GF7) of ER
      membrane localization. Consistent with the human UniProt topology and with the
      electronic, ComplexPortal, and Reactome ER-membrane annotations.
    action: ACCEPT
    reason: Correct localization, corroborated by orthology and by the human single-pass
      type I ER membrane topology.
    supported_by:
    - reference_id: file:human/PIGX/PIGX-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162830
  qualifier: located_in
  review:
    summary: Reactome traceable assertion placing the PIG-M/PIG-X-catalyzed addition
      of the first mannose to glucosaminyl-acyl-PI at the lumenal surface of the ER
      membrane. Consistent with all other ER-membrane annotations for PIGX.
    action: ACCEPT
    reason: Correct localization from an authoritative pathway resource; matches the
      UniProt ER topology and the complex's lumenal ER activity.
    supported_by:
    - reference_id: Reactome:R-HSA-162830
      supporting_text: The reaction takes place at the lumenal surface of the endoplasmic
        reticulum membrane
    - reference_id: Reactome:R-HSA-162830
      supporting_text: It is catalyzed by a complex of at least two components, PIG-M
        and PIG-X
core_functions:
- description: PIGX is the non-catalytic stabilizing subunit of GPI mannosyltransferase
    I (GPI-MT-I); it binds and stabilizes the catalytic mannosyltransferase PIGM and
    is required for the first-mannose-addition step of GPI-anchor biosynthesis, acting
    as part of the GPI-MT-I complex on the lumenal side of the ER membrane. PIGX itself
    has no characterized catalytic activity, so no molecular_function term is asserted.
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  supported_by:
  - reference_id: PMID:32156170
    supporting_text: PIGM functions in association with PIGX, which stabilizes PIGM
  - reference_id: file:human/PIGX/PIGX-uniprot.txt
    supporting_text: Probably acts by stabilizing the mannosyltransferase PIGM.
proposed_new_terms: []
suggested_questions:
- question: Does PIGX have any function beyond stabilizing PIGM (e.g. substrate presentation
    or lipid recognition within GPI-MT-I), or is protecting PIGM from degradation its
    sole role?
suggested_experiments:
- description: Structural determination of the human PIGM-PIGX GPI-MT-I complex to
    define how PIGX binds and stabilizes PIGM and whether it contributes to Dol-P-Man
    or GlcN-(acyl)PI recognition.
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:32156170
  title: Biosynthesis and biology of mammalian GPI-anchored proteins.
  findings:
  - statement: PIGM (GPI-MTI) adds the first GPI mannose and functions in association
      with PIGX, which stabilizes PIGM; the core GPI is assembled on the ER membrane.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative Kinoshita review; full text available and directly
      states PIGX's role as the stabilizing (regulatory) subunit of GPI-MTI that stabilizes
      catalytic PIGM. Also the ComplexPortal-cited reference for the ER-membrane and
      GPI-MT-I complex annotations.
- id: Reactome:R-HSA-162830
  title: glucosaminyl-acyl-PI + dolichol phosphate D-mannose -> mannose(al1-4)glucosaminyl-acyl-PI
    + dolichol phosphate
  findings:
  - statement: Reactome reaction for the first-mannose addition to glucosaminyl-acyl-PI,
      catalyzed by a complex of PIG-M and PIG-X at the lumenal surface of the ER membrane.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction cited by GOA for PIGX ER-membrane localization;
      describes the PIGM/PIGX-catalyzed GPI-MT-I step and names both subunits.
- id: file:human/PIGX/PIGX-uniprot.txt
  title: UniProtKB Q8TBF5 PIGX record
  findings:
  - statement: UniProt describes PIGX as the stabilizing subunit of the GPI-mannosyltransferase
      I complex (with PIGM) that probably acts by stabilizing PIGM, a single-pass type
      I ER membrane protein participating in GPI-anchor biosynthesis.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt record for Q8TBF5; used for the subunit-stabilization function,
      subcellular location, and single-pass type I membrane topology statements.