id: Q9Y2B2
gene_symbol: PIGL
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGL is the N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (PIG-L,
  EC 3.5.1.89) that catalyzes the second step of glycosylphosphatidylinositol (GPI) anchor
  biosynthesis. It hydrolyzes N-acetylglucosaminyl-phosphatidylinositol (GlcNAc-PI) to
  glucosaminyl-phosphatidylinositol (GlcN-PI) plus acetate, a de-N-acetylation that is a
  prerequisite for the subsequent inositol acylation and mannosylation steps of GPI
  assembly. It is a single-pass type I endoplasmic reticulum membrane protein with a large
  cytoplasmic domain and belongs to the PIGL/LmbE-like deacetylase family. Biallelic
  loss-of-function or hypomorphic PIGL variants cause CHIME syndrome (Zeman-Sheard syndrome),
  an inherited GPI-deficiency disorder characterized by coloboma, congenital heart disease,
  ichthyosiform dermatosis, impaired intellectual development, and ear anomalies.
alternative_products:
- name: '1'
  id: Q9Y2B2-1
- name: '2'
  id: Q9Y2B2-2
  sequence_note: VSP_056886
existing_annotations:
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (PAN-GO) inference of the core catalytic function, GlcNAc-PI
      de-N-acetylase activity. This is the correct and experimentally supported molecular
      function for PIGL and matches the enzyme identity (EC 3.5.1.89).
    action: ACCEPT
    reason: The GlcNAc-PI de-N-acetylase activity is the defining function of PIGL and is
      directly supported by experimental work; the IBA inference across the conserved PIGL
      family (including yeast Gpi12p) is well founded.
    supported_by:
    - reference_id: PMID:10085243
      supporting_text: The second step of GPI biosynthesis is
    - reference_id: PMID:14742432
      supporting_text: catalyzed by N-acetylglucosaminylphosphatidylinositol deacetylase (PIG-L).
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that PIGL is active in the endoplasmic reticulum. This
      is correct but is the broader compartment term; the more informative cellular
      component is the ER membrane (GO:0005789), where PIGL is experimentally localized.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but less specific than the experimentally supported ER
      membrane annotation. Retained as a valid, broader is_active_in statement while the
      ER membrane term captures the informative location.
    supported_by:
    - reference_id: PMID:14742432
      supporting_text: activity is localized to the endoplasmic reticulum (ER) but enriched in a
    - reference_id: file:human/PIGL/PIGL-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the deacetylase molecular function via UniRule/ARBA,
      RHEA:11660 and EC:3.5.1.89. Correct and consistent with the experimental evidence.
    action: ACCEPT
    reason: The IEA mapping to GO:0000225 (EC 3.5.1.89 / RHEA:11660) is the correct catalytic
      term and agrees with experimental and phylogenetic evidence.
    supported_by:
    - reference_id: file:human/PIGL/PIGL-uniprot.txt
      supporting_text: Catalyzes the second step of glycosylphosphatidylinositol
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation (ARBA / UniProtKB-SubCell SL-0097) placing PIGL in the ER
      membrane. Correct and matches the experimental IDA/EXP localization.
    action: ACCEPT
    reason: The ER membrane location is experimentally established for human PIGL, a
      single-pass type I ER membrane protein; the IEA is consistent and correct.
    supported_by:
    - reference_id: file:human/PIGL/PIGL-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
    - reference_id: PMID:14742432
      supporting_text: We show that human PIG-L is a 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 (ARBA / UniPathway UPA00196) placing PIGL in GPI anchor
      biosynthesis. PIGL performs the second, obligatory step of this pathway.
    action: ACCEPT
    reason: GPI anchor biosynthetic process is the core biological process for PIGL; the
      de-N-acetylation it catalyzes is a required step of GPI assembly.
    supported_by:
    - reference_id: file:human/PIGL/PIGL-uniprot.txt
      supporting_text: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor
    - reference_id: PMID:10085243
      supporting_text: The second step of GPI biosynthesis is
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162710
  qualifier: involved_in
  review:
    summary: Reactome traceable annotation to the overall GPI synthesis pathway. Correct;
      PIGL catalyzes the second reaction of this ER pathway.
    action: ACCEPT
    reason: PIGL is a bona fide component of the GPI anchor biosynthetic pathway curated by
      Reactome (Synthesis of glycosylphosphatidylinositol).
    supported_by:
    - reference_id: Reactome:R-HSA-162710
      supporting_text: GPI is synthesized in the endoplasmic reticulum.
    - reference_id: Reactome:R-HSA-162857
      supporting_text: In the second step of GPI synthesis, N-acetylglucosaminyl-PI is hydrolyzed
        to yield glucosaminyl-PI and acetate.
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162857
  qualifier: enables
  review:
    summary: Reactome traceable annotation of the second-step deacetylase reaction
      (N-acetylglucosaminyl-PI + H2O -> glucosaminyl-PI + acetate) catalyzed by PIG-L.
      Correct core molecular function.
    action: ACCEPT
    reason: The Reactome reaction curation directly attributes the GlcNAc-PI de-N-acetylase
      activity to PIG-L, matching the experimental and phylogenetic evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-162857
      supporting_text: as is the PIG-L enzyme that catalyzes it
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: EXP
  original_reference_id: PMID:14742432
  qualifier: enables
  review:
    summary: Experimental demonstration of GlcNAc-PI de-N-acetylase activity for human PIG-L
      (Pottekat & Menon 2004), which characterized the activity and its ER localization.
      This is the strongest, experiment-based support for the core molecular function.
    action: ACCEPT
    reason: Direct experimental evidence in human cells that PIG-L catalyzes GlcNAc-PI
      de-N-acetylation; represents the core catalytic function.
    supported_by:
    - reference_id: PMID:14742432
      supporting_text: catalyzed by N-acetylglucosaminylphosphatidylinositol deacetylase (PIG-L).
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:10085243
  qualifier: located_in
  review:
    summary: ER membrane localization supported in the original PIG-L characterization; the
      de-N-acetylation step and its enzyme are components of the ER GPI machinery.
    action: ACCEPT
    reason: ER membrane localization is correct and independently confirmed by the
      experimental study of Pottekat & Menon (PMID:14742432); PIGL is a single-pass ER
      membrane protein.
    supported_by:
    - reference_id: PMID:14742432
      supporting_text: We show that human PIG-L is a type I membrane protein
    - reference_id: file:human/PIGL/PIGL-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer (from mouse ortholog O35790) of the deacetylase
      molecular function. Correct and redundant with the experimental evidence.
    action: ACCEPT
    reason: The ISS transfer of GO:0000225 from the conserved rodent ortholog is correct and
      matches the experimentally established human activity.
    supported_by:
    - reference_id: PMID:10085243
      supporting_text: has GlcNAc-PI de-N-acetylase activity in vitro
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:14742432
  qualifier: located_in
  review:
    summary: Direct assay localizing human PIG-L and its GlcNAc-PI de-N-acetylase activity
      to the ER membrane (Pottekat & Menon 2004), including identification of ER retention
      signals. Core cellular component.
    action: ACCEPT
    reason: Direct experimental evidence that PIG-L is an ER membrane protein; the most
      informative and best-supported cellular component annotation.
    supported_by:
    - reference_id: PMID:14742432
      supporting_text: activity is localized to the endoplasmic reticulum (ER) but enriched in a
    - reference_id: PMID:14742432
      supporting_text: We show that human PIG-L is a type I membrane protein
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:10085243
  qualifier: involved_in
  review:
    summary: Functional/complementation evidence (Watanabe et al. 1999) that PIG-L is
      required for GPI biosynthesis - the rat gene was cloned by complementing a CHO mutant
      defective in the second step, and its yeast homologue Gpi12p is essential for GPI and
      cell viability. Core biological process.
    action: ACCEPT
    reason: Loss/restoration of GlcNAc-PI de-N-acetylase activity and cell-surface
      GPI-anchored protein expression on manipulating PIG-L/Gpi12p demonstrates PIGL's
      required role in GPI anchor biosynthesis.
    supported_by:
    - reference_id: PMID:10085243
      supporting_text: the cell-surface expression of GPI-anchored proteins and GlcNAc-PI
    - reference_id: PMID:10085243
      supporting_text: indispensable in yeasts
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162857
  qualifier: located_in
  review:
    summary: Reactome traceable annotation placing the PIG-L enzyme and its substrates in
      the ER membrane for the second-step reaction. Correct.
    action: ACCEPT
    reason: Consistent with the experimental ER membrane localization; Reactome curates the
      reaction as occurring in the ER membrane with PIG-L as the catalyst.
    supported_by:
    - reference_id: Reactome:R-HSA-162857
      supporting_text: as is the PIG-L enzyme that catalyzes it
- term:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  evidence_type: NAS
  original_reference_id: PMID:10085243
  qualifier: enables
  review:
    summary: Non-traceable/author-statement annotation of the deacetylase molecular function
      from the original PIG-L paper (Watanabe et al. 1999), which established GlcNAc-PI
      de-N-acetylase activity for recombinant PIG-L. Correct core function.
    action: ACCEPT
    reason: The molecular function is correct and is directly supported by the enzymatic
      assays in this reference and by later human EXP evidence (PMID:14742432).
    supported_by:
    - reference_id: PMID:10085243
      supporting_text: has GlcNAc-PI de-N-acetylase activity in vitro
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: NAS
  original_reference_id: PMID:10085243
  qualifier: involved_in
  review:
    summary: Author-statement annotation of involvement in GPI biosynthesis from the
      original PIG-L characterization. Correct core biological process.
    action: ACCEPT
    reason: PIG-L catalyzes the essential second step of GPI biosynthesis; the process
      annotation is well supported by the same reference and by disease genetics
      (CHIME/GPI-deficiency).
    supported_by:
    - reference_id: PMID:10085243
      supporting_text: The second step of GPI biosynthesis is
    - reference_id: PMID:10085243
      supporting_text: indispensable in yeasts
core_functions:
- description: N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (EC 3.5.1.89)
    catalyzing the second step of GPI anchor biosynthesis in the ER membrane - hydrolysis of
    GlcNAc-PI to GlcN-PI plus acetate.
  molecular_function:
    id: GO:0000225
    label: N-acetylglucosaminylphosphatidylinositol deacetylase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:14742432
    supporting_text: catalyzed by N-acetylglucosaminylphosphatidylinositol deacetylase (PIG-L).
  - reference_id: PMID:10085243
    supporting_text: The second step of GPI biosynthesis is
  - reference_id: file:human/PIGL/PIGL-uniprot.txt
    supporting_text: Catalyzes the second step of glycosylphosphatidylinositol
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:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10085243
  title: Mammalian PIG-L and its yeast homologue Gpi12p are N-acetylglucosaminylphosphatidylinositol
    de-N-acetylases essential in glycosylphosphatidylinositol biosynthesis.
  findings:
  - statement: Recombinant PIG-L has GlcNAc-PI de-N-acetylase activity in vitro, and the
      de-N-acetylation second step of GPI biosynthesis is conserved and essential from yeast
      (Gpi12p) to mammals.
    supporting_text: has GlcNAc-PI de-N-acetylase activity in vitro
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original cloning/functional paper for PIG-L (rat gene complementing a CHO
      mutant defective in the second step); abstract-only in cache but directly establishes
      the deacetylase activity and its essential role in GPI biosynthesis. Cited by GOA as
      NAS (MF) and IMP (BP).
- id: PMID:14742432
  title: Subcellular localization and targeting of N-acetylglucosaminyl phosphatidylinositol
    de-N-acetylase, the second enzyme in the glycosylphosphatidylinositol biosynthetic
    pathway.
  findings:
  - statement: Human PIG-L is a single-pass type I ER membrane protein whose GlcNAc-PI
      de-N-acetylase activity is localized to the endoplasmic reticulum, retained there by a
      multi-component localization signal.
    supporting_text: We show that human PIG-L is a type I membrane protein
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human enzyme-activity and ER-membrane localization/topology paper;
      abstract-only in cache but explicitly assays human PIG-L. Supports the EXP MF and
      EXP/IDA ER membrane annotations.
- id: Reactome:R-HSA-162710
  title: Synthesis of glycosylphosphatidylinositol (GPI)
  findings:
  - statement: GPI is synthesized in the endoplasmic reticulum via a pathway of nine
      reactions; PIGL contributes the second reaction.
    supporting_text: GPI is synthesized in the endoplasmic reticulum.
- id: Reactome:R-HSA-162857
  title: N-acetylglucosaminyl-PI + H2O -> glucosaminyl-PI + acetate
  findings:
  - statement: The second GPI-synthesis reaction hydrolyzes N-acetylglucosaminyl-PI to
      glucosaminyl-PI and acetate in the ER membrane, catalyzed by PIG-L.
    supporting_text: as is the PIG-L enzyme that catalyzes it
- id: file:human/PIGL/PIGL-uniprot.txt
  title: UniProtKB Q9Y2B2 (PIGL_HUMAN)
  findings:
  - statement: PIGL catalyzes the second step of GPI biosynthesis (de-N-acetylation of
      GlcNAc-PI) and is an ER membrane, single-pass type I membrane protein of the PIGL
      family; variants cause CHIME syndrome.
    supporting_text: Catalyzes the second step of glycosylphosphatidylinositol