Affinage

PIGT

GPI-anchor transamidase component PIGT · UniProt Q969N2

Length
578 aa
Mass
65.7 kDa
Annotated
2026-06-10
70 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIGT (PIG-T) is an essential subunit of the endoplasmic reticulum-localized GPI transamidase complex that transfers preassembled glycosylphosphatidylinositol (GPI) anchors onto proteins bearing a C-terminal GPI signal peptide (PMID:11483512). Within this complex PIG-T physically associates with GAA1, GPI8, and PIG-S, and stabilizes the assembly by maintaining the expression levels of GAA1 and GPI8; its loss abolishes GPI transfer specifically by blocking formation of the carbonyl intermediates of transamidation (PMID:11483512). PIG-T forms an intermolecular disulfide bond with GPI8 between conserved cysteines that, while not absolutely required, is needed for full transamidase activity (PMID:12582175). PIG-T is a type I membrane glycoprotein retained in the ER through a dominant retention signal within its transmembrane span (PMID:15713669). Loss-of-function and hypomorphic PIGT variants reduce surface expression of GPI-anchored proteins and cause human disease: biallelic mutations impair GPI anchor attachment in patients (PMID:23636107, PMID:24906948), and a germline-plus-somatic two-hit loss of PIGT in hematopoietic cells causes paroxysmal nocturnal hemoglobinuria, establishing that defective GPI transfer—rather than defective GPI synthesis—is sufficient to produce the PNH phenotype (PMID:23733340). Beyond its canonical transamidase role, PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells, enhancing proliferation, oxidative phosphorylation, glycolysis, and metastasis, and its mRNA is stabilized by WTAP-deposited m6A marks read by IGF2BP2 (PMID:38169393).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    Established that PIG-T is an obligatory subunit of the GPI transamidase complex and defined its biochemical role, answering whether GPI transfer to proteins requires a dedicated multi-subunit machine and which step PIG-T governs.

    Evidence Homologous recombination knockout in mouse F9 cells with co-immunoprecipitation and in vitro transamidase assay

    PMID:11483512

    Open questions at the time
    • Did not resolve the atomic-level architecture of the complex
    • Mechanism by which PIG-T maintains GAA1/GPI8 expression not defined
    • Precise catalytic contribution of PIG-T versus GPI8 not separated
  2. 2003 High

    Identified a functional disulfide bond between PIG-T and GPI8, addressing how subunits are covalently coupled to support catalysis.

    Evidence Cys→Ser site-directed mutagenesis with in vitro transamidase assay and cell-based rescue

    PMID:12582175

    Open questions at the time
    • Disulfide is not absolutely required, so its precise contribution to activity is partial
    • Structural geometry of the bonded cysteines not determined
  3. 2005 High

    Mapped the determinant of PIG-T subcellular residence, answering how the transamidase is confined to the ER where GPI transfer occurs.

    Evidence Transmembrane domain fusion to Tac antigen with subcellular localization analysis in a domain-swap design

    PMID:15713669

    Open questions at the time
    • Trafficking receptors recognizing the TM retention signal not identified
    • Whether complex assembly contributes to retention not addressed
  4. 2013 Medium

    Connected PIGT loss-of-function to human disease and demonstrated in vivo that point mutations abolish transamidase function, beyond cell-surface marker readouts.

    Evidence Flow cytometry of patient granulocytes plus zebrafish morpholino knockdown and human mRNA rescue (p.Thr183Pro fails to rescue)

    PMID:23636107

    Open questions at the time
    • Single mutation tested in vivo
    • Molecular basis of how p.Thr183Pro impairs activity not resolved
  5. 2013 Medium

    Showed that defective GPI anchor transfer to proteins, not defective GPI synthesis, is sufficient to cause paroxysmal nocturnal hemoglobinuria, reframing the pathogenic spectrum of GPI deficiency.

    Evidence Deep sequencing of GPI pathway genes identifying a germline splice-site plus somatic second-hit deletion in patient granulocytes

    PMID:23733340

    Open questions at the time
    • Single patient case
    • No direct enzymatic assay of the variant alleles
  6. 2014 Medium

    Distinguished null versus hypomorphic PIGT alleles through rescue, clarifying the genotype-function relationship underlying patient phenotypes.

    Evidence Flow cytometry of patient granulocytes plus transfection rescue of mutants into PIGT-deficient cells (p.Arg488Trp partial, p.Glu84* null)

    PMID:24906948

    Open questions at the time
    • No direct enzymatic kinetics for hypomorphic allele
    • Single lab
  7. 2022 Low

    Extended the catalogue of pathogenic PIGT variants impairing surface GPI-AP display.

    Evidence Flow cytometry quantification of cell-surface GPI-APs on patient-derived cells for p.Gly360Val

    PMID:27916860

    Open questions at the time
    • Single method (flow cytometry), no direct enzymatic assay
    • Mechanism of activity reduction not defined
  8. 2023 Medium

    Quantified the functional impact of an additional variant using a defined knockout-rescue system, refining variant interpretation.

    Evidence Transfection rescue into PIGT knockout HEK293 cells with FACS readout of GPI-AP surface expression (p.Arg507Trp mildly reduced)

    PMID:36970549

    Open questions at the time
    • Single method
    • Structural basis of mild reduction not addressed
  9. 2024 Medium

    Revealed a non-canonical, disease-relevant role for PIGT in cancer metabolism via GLUT1 glycosylation, and identified an upstream m6A regulatory axis controlling PIGT mRNA stability.

    Evidence PIGT silencing/overexpression, CCK-8/colony/Transwell assays, Seahorse flux analysis, immunoblot, and in vivo tumor model in bladder cancer

    PMID:38169393

    Open questions at the time
    • Whether GLUT1 glycosylation occurs through canonical transamidase activity or another mechanism not resolved
    • Single lab
    • Generality across cancer types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the catalytic step and subunit coordination of the transamidase are organized at atomic resolution, and how individual missense variants map onto this architecture to graded loss-of-function, remains open.
  • No structural model of PIG-T within the assembled complex in the corpus
  • Mechanism linking PIG-T to GLUT1 trafficking versus canonical transamidation unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-392499 Metabolism of proteins 1
Partners
GAA1GPI8PIGS
Complex memberships
GPI transamidase complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PIG-T (PIGT) is an essential subunit of the GPI transamidase complex. Knockout of PIGT in mouse F9 cells abolished transfer of GPI to proteins, specifically blocking formation of the carbonyl intermediates required for transamidation. PIG-T forms a protein complex with GAA1, GPI8, and PIG-S, and PIG-T stabilizes the complex by maintaining expression levels of GAA1 and GPI8. Homologous recombination knockout in mouse F9 cells, co-immunoprecipitation, in vitro transamidase assay The EMBO journal High 11483512
2003 GPI8 and PIG-T (PIGT) form a functionally important intermolecular disulfide bond between conserved cysteine residues within the GPI transamidase complex. Mutation of the relevant cysteines to serines in either GPI8 or PIG-T markedly reduced in vitro transamidase activity and failed to fully restore surface expression of GPI-anchored proteins in respective mutant cells. The disulfide bond is not absolutely required but is needed for full transamidase activity. Site-directed mutagenesis (Cys→Ser), in vitro transamidase assay, transfection rescue experiments, antibody-based detection of disulfide bond formation The Journal of biological chemistry High 12582175
2005 PIG-T (PIGT) is localized to the endoplasmic reticulum (ER) and its ER retention is mediated by information within its transmembrane span. Fusion of the PIG-T transmembrane domain to Tac antigen (a plasma membrane protein) caused the fusion protein to be retained in the ER, indicating a dominant ER-retention signal in the PIG-T TM domain. PIG-T is a type I membrane glycoprotein. Fusion protein construction, subcellular localization by imaging/fractionation, domain-swap experiments The Journal of biological chemistry High 15713669
2013 A homozygous missense mutation in PIGT (c.547A>C, p.Thr183Pro) causes reduced surface expression of GPI-anchored protein CD16b on patient granulocytes. The mutant p.Thr183Pro PIGT mRNA failed to rescue gastrulation defects induced by morpholino knockdown of the PIGT ortholog in zebrafish, whereas wild-type human PIGT mRNA could rescue, establishing this mutation as a loss-of-function variant that impairs GPI transamidase activity in vivo. Flow cytometry of patient granulocytes, morpholino knockdown and mRNA rescue in zebrafish embryos Journal of medical genetics Medium 23636107
2013 Loss of PIGT function (via a germline splice-site mutation plus somatic deletion of the second allele) in hematopoietic stem cells causes deficiency of GPI-anchored complement regulatory proteins (CD55, CD59) on blood cells, leading to paroxysmal nocturnal hemoglobinuria (PNH). This establishes that defective GPI anchor transfer to proteins (rather than defective GPI synthesis) is sufficient to cause PNH. Next-generation deep sequencing of all GPI pathway genes, identification of germline + somatic two-hit mechanism in patient granulocytes Blood Medium 23733340
2014 Compound heterozygous PIGT mutations (p.Glu84* and p.Arg488Trp) reduce surface expression of GPI-anchored proteins DAF and CD59 on patient granulocytes. Transfection of the p.Arg488Trp mutant PIGT into PIGT-deficient cells partially restored GPI-AP expression, while the p.Glu84* (null) mutant did not, demonstrating that p.Arg488Trp is a hypomorphic allele and that PIGT is required for GPI anchor attachment to proteins. Flow cytometry of patient granulocytes, transfection rescue into PIGT-deficient cells Neurogenetics Medium 24906948
2022 A homozygous PIGT variant p.Gly360Val leads to reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface of patient-derived cells, confirming the pathogenic role of this variant in impairing GPI transamidase function. In vitro cell surface GPI-AP quantification by flow cytometry on cells from affected patients Genes Low 27916860
2023 The PIGT variant p.Arg507Trp leads to mildly reduced GPI transamidase activity, as demonstrated by FACS analysis of PIGT knockout HEK293 cells transfected with wild-type or p.Arg507Trp mutant cDNA constructs measuring surface GPI-AP expression. Transfection rescue into PIGT knockout HEK293 cells, FACS analysis of GPI-AP surface expression Frontiers in neurology Medium 36970549
2024 PIGT promotes GLUT1 glycosylation and membrane trafficking in bladder cancer cells. Overexpression of PIGT enhanced cell proliferation, oxidative phosphorylation, glycolysis, and tumor metastasis in vivo through activation of GLUT1. PIGT is post-translationally regulated by WTAP-mediated m6A modification of its mRNA, with IGF2BP2 reading the m6A mark to stabilize PIGT mRNA. PIGT silencing/overexpression, CCK-8/colony formation/Transwell assay, Seahorse metabolic flux analysis, immunoblot, RT-PCR, in vivo tumor model Journal of translational medicine Medium 38169393

Source papers

Stage 0 corpus · 70 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1973 Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. The Journal of experimental medicine 1173 4542806
1973 Function of macrophages in antigen recognition by guinea pig T lymphocytes. II. Role of the macrophage in the regulation of genetic control of the immune response. The Journal of experimental medicine 527 4126770
1977 Immune response gene control of determinant selection. I. Intramolecular mapping of the immunogenic sites on insulin recognized by guinea pig T and B cells. The Journal of experimental medicine 160 95787
2001 PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. The EMBO journal 143 11483512
2013 A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. Journal of medical genetics 109 23636107
2013 Human dominant-negative class II transactivator transgenic pigs - effect on the human anti-pig T-cell immune response and immune status. Immunology 94 23566228
1977 Independent populations of primed F1 guinea pig T lymphocytes respond to antigen-pulsed parental peritoneal exudate cells. The Journal of experimental medicine 89 233906
1976 The function of macrophages in antigen recognition by guinea pig T lymphocytes. III. Genetic analysis of the antigens mediating macrophage-T lymphocyte interaction. Journal of immunology (Baltimore, Md. : 1950) 89 1083875
2005 A GntR family transcriptional regulator (PigT) controls gluconate-mediated repression and defines a new, independent pathway for regulation of the tripyrrole antibiotic, prodigiosin, in Serratia. Microbiology (Reading, England) 78 16339930
1985 Production of monoclonal antibodies defining guinea pig T-cell surface markers and a strain 13 Ia-like antigen: the value of immunohistological screening. Hybridoma 72 3891587
2003 Two subunits of glycosylphosphatidylinositol transamidase, GPI8 and PIG-T, form a functionally important intermolecular disulfide bridge. The Journal of biological chemistry 68 12582175
2013 A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood 62 23733340
2014 Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3. Neurogenetics 59 24906948
1987 Neuropeptide regulation of human thymocyte, guinea pig T lymphocyte and rat B lymphocyte mitogenesis. International archives of allergy and applied immunology 57 3498694
1981 Fine specificity of genetic regulation of guinea pig T lymphocyte responses to angiotensin II and related peptides. The Journal of experimental medicine 52 6166702
2004 Th-1/Th-2 type cytokine profiles of pig T-cells cultured with antigen-treated monocyte-derived dendritic cells. Vaccine 46 15161079
2015 Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors. Molecular genetics and metabolism 43 25943031
1984 Non-activated guinea-pig T cells and thymocytes express Ia antigens: FACS analysis with alloantibodies and monoclonal antibodies. Immunology 42 6197362
1976 The inhibition of cutaneous basophil hypersensitivity reactions by a heterologous anti-guinea pig T cell serum. Journal of immunology (Baltimore, Md. : 1950) 34 58042
2017 Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and PIGT mutations. Brain & development 25 28728837
2019 PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics. Genetics in medicine : official journal of the American College of Medical Genetics 24 30976099
2016 Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype. Genes 23 27916860
2012 Ex-vivo expanded baboon CD4+ CD25 Hi Treg cells suppress baboon anti-pig T and B cell immune response. Xenotransplantation 23 22497512
2024 PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking. Journal of translational medicine 21 38169393
2018 Homozygous PIGT Mutation Lead to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3. Frontiers in genetics 21 29868109
2021 HLA-G1+ Expression in GGTA1KO Pigs Suppresses Human and Monkey Anti-Pig T, B and NK Cell Responses. Frontiers in immunology 19 34566993
2016 Modified glycan models of pig-to-human xenotransplantation do not enhance the human-anti-pig T cell response. Transplant immunology 18 26873419
1978 Visualization of a guinea pig T lymphocyte surface component cross-reactive with immunoglobulin. Science (New York, N.Y.) 17 74094
1980 Augmentation of guinea pig T lymphocyte proliferative response to antigens in the presence of purified B cells. International archives of allergy and applied immunology 16 6965491
1985 Characterization of pig T cell growth factor and its species-restricted activity on human, mouse and sheep cells. Veterinary immunology and immunopathology 15 3927570
1983 Identification and characterization of gp TFA-1, a guinea pig T cell surface antigen associated with T cell function. Journal of immunology (Baltimore, Md. : 1950) 15 6411814
1976 Induction of specific anti-guinea pig T cell sera in rabbits. Journal of immunological methods 15 1082461
2018 Recurrent aseptic meningitis with PIGT mutations: a novel pathogenesis of recurrent meningitis successfully treated by eculizumab. BMJ case reports 14 30262533
2016 Characterization of guinea pig T cell responses elicited after EP-assisted delivery of DNA vaccines to the skin. Vaccine 14 27894716
2005 Neutralization of tumor necrosis factor alpha suppresses antigen-specific type 1 cytokine responses and reverses the inhibition of mycobacterial survival in cocultures of immune guinea pig T lymphocytes and infected macrophages. Infection and immunity 14 16299346
1988 Behaviour of guinea pig T cells stimulated by antigen, allo-antigen and mitogen. International archives of allergy and applied immunology 13 2973441
1978 Specificity of pig T lymphocyte antiserum: cytotoxicity and inhibiting properties onto E-rosette-forming lymphocytes. Annales d'immunologie 13 308791
2005 TRAV gene usage in pig T-cell receptor alpha cDNA. Immunogenetics 12 15900493
2019 Role of human and porcine MHC DRB1 alleles in determining the intensity of individual human anti-pig T-cell responses. Xenotransplantation 11 31074044
1981 Characterization of an antiserum to guinea pig antithrombin III (AT III). I. Reactivity with guinea pig T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 11 6167623
1992 Analysis of mature guinea pig T cells with a monoclonal antibody directed against a framework determinant of the T-cell receptor for antigen. Scandinavian journal of immunology 10 1384115
1979 The activation of guinea pig T lymphocytes by anti-beta 2-microglobulin serum. Journal of immunology (Baltimore, Md. : 1950) 10 87432
2005 Endoplasmic reticulum localization of Gaa1 and PIG-T, subunits of the glycosylphosphatidylinositol transamidase complex. The Journal of biological chemistry 9 15713669
2021 Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures. Frontiers in genetics 8 34046058
2021 Human-like Response of Pig T Cells to Superagonistic Anti-CD28 Monoclonal Antibodies. Journal of immunology (Baltimore, Md. : 1950) 8 34625520
2020 Evidence of the milder phenotypic spectrum of c.1582G>A PIGT variant: Delineation based on seven novel Polish patients. Clinical genetics 8 32725661
1992 Subpopulations of guinea-pig T lymphocytes defined by isoforms of the leucocyte common antigen. Immunology 8 1362184
1984 Endogenous surface phosphorylation reactions and ectokinase activity in the guinea pig T lymphocyte. Cellular immunology 7 6331892
1984 Analysis of a sheep anti-pig T lymphoblast serum with specificity for E rosette-forming lymphocytes. Veterinary immunology and immunopathology 7 6334394
2019 Case report of a child bearing a novel deleterious splicing variant in PIGT. Medicine 6 30813157
1988 Characterization of a monoclonal antibody to guinea pig T cells that inhibits rosette formation of the cells with rabbit erythrocytes: similarity of the antigen to E-receptor on human T cells. Microbiology and immunology 6 2897618
1985 Guinea pig T lymphocyte development analyzed by enzyme histocytochemistry, monoclonal antibodies, and flow cytometry. Laboratory investigation; a journal of technical methods and pathology 6 2579290
2003 Effector functions of CD8-positive guinea pig T lymphocytes. Cellular immunology 5 12826083
1981 Isotype specificity of Fc gamma-receptors on guinea-pig T lymphocytes and their modulation by homologous immune complexes. Immunology 5 6970721
1977 Alkaline phosphate in the differentiation of guinea pig T lymphocytes. Acta pathologica et microbiologica Scandinavica. Section C, Immunology 5 303434
2022 The Organization of the Pig T-Cell Receptor γ (TRG) Locus Provides Insights into the Evolutionary Patterns of the TRG Genes across Cetartiodactyla. Genes 4 35205222
2022 Allogeneic stem cell transplantation-A curative treatment for paroxysmal nocturnal hemoglobinuria with PIGT mutation: A case report. World journal of clinical cases 4 35979111
1989 The generation of guinea pig T-cell lines reactive to antigens from Mycobacterium tuberculosis. Selected lines induce erythematous skin reactions. Scandinavian journal of immunology 4 2470134
1981 Dependence on macrophages of the guinea pig T-cell immune response to Herpetomonas samuelpessoai. The Journal of parasitology 4 6973620
1996 Identification and characterization of a high-affinity leukotriene B4 receptor on guinea pig T lymphocytes and its regulation by lipoxin A4. The Journal of pharmacology and experimental therapeutics 3 8627545
1982 Characterization of a 75,000 mol. wt glycoprotein synthesized by guinea-pig T-lymphocytes: a possible homologue of Lyt-1 antigen. Molecular immunology 3 6984489
2023 Case report: Functional analysis of the p.Arg507Trp variant of the PIGT gene supporting the moderate epilepsy phenotype of mutations in the C-terminal region. Frontiers in neurology 2 36970549
2021 Compound Heterozygous PIGT Mutations in Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome: First Case in Korea and Characterization by Persistent Hypophosphatasia. Annals of clinical and laboratory science 2 34162574
1978 Separation of RRBC-RFC and non-rosette forming cells (non-RFC) of guinea pig T-cell populations and their functional difference. 1. Response of RRBC-RFC and non-RFC to either Con-A or LPS. Microbiology and immunology 2 310944
2025 A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient. International journal of molecular sciences 0 40141433
2025 The transcription factor HOXB7 significantly enhances the expression of PIGT through the Wnt/β-catenin signaling pathway, thereby promoting the proliferation and deterioration of HCC. Expert review of anticancer therapy 0 40808272
2024 Spectrum of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (MCAHS3) Due to Phosphatidylinositol Glycan Biosynthesis Class T (PIGT) Gene Mutations: A Narrative Review. Cureus 0 38903302
2023 [Genetic analysis and prenatal diagnosis of a child with Multiple congenital malformations-hypotonia-epilepsy syndrome type 3 due to variants of PIGT gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 37643962
2003 Modulation of human anti-pig T cell responses by monoclonal antibodies directed to porcine CD45 molecules. Annals of transplantation 0 15114937
1981 [Changes of guinea pig T lymphocytes after E rosette formation -expression of Fc and complement receptors-(author's transl)]. [Hokkaido igaku zasshi] The Hokkaido journal of medical science 0 6976298

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