Affinage

GLIPR2

Golgi-associated plant pathogenesis-related protein 1 · UniProt Q9H4G4

Length
154 aa
Mass
17.2 kDa
Annotated
2026-06-10
24 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLIPR2 (GAPR-1) is an N-myristoylated, Golgi-associated member of the CAP/PR-1 superfamily that acts as a negative regulator of autophagy and a driver of mesenchymal transition programs (PMID:15123429, PMID:33222586). Its 1.55 Å crystal structure established structural homology to PR-1 family proteins and showed that it forms homodimers, with a potential catalytic triad across the dimer interface (PMID:15123429). The protein binds negatively charged phospholipid membranes, preferring phosphatidic acid, and is stably anchored through combined electrostatic interactions and N-terminal myristoylation (PMID:20095951). Mechanistically, GLIPR2 inhibits autophagy by directly binding BECN1 residues 267–284 through a conserved equatorial groove; mutagenesis of five groove-lining residues abrogates this interaction, and depletion of GLIPR2 increases autophagic flux, PtdIns3P generation, and WIPI2 recruitment, with purified GLIPR2 directly inhibiting PtdIns3K-C1 lipid kinase activity in vitro (PMID:28876241, PMID:33222586). Dimerization occludes the BECN1-binding groove, providing a structural switch that couples oligomeric state to inhibitory function (PMID:28876241). GLIPR2 also drives epithelial-to-mesenchymal transition in renal and hepatocellular cells via ERK1/2 signaling (PMID:23516513, PMID:24204846), drives EndoMT and cardiac fibrosis through PDGFRL/AKT/mTOR (PMID:40543810), and is stabilized by SMYD2-mediated methylation upstream of an ERK/p38 EMT program (PMID:38879290). Additional functions include IRAK1-dependent phosphorylation at Ser58 that promotes TMED7 binding to enhance TLR4-driven IFN-β signaling (PMID:26678074), N-myristoylation-dependent pro-ferroptotic activity (PMID:41782991), and metal-ion- and redox-regulated amyloid-like assembly through zinc binding at His54/His103 versus a copper/disulfide-dependent pathway (PMID:30700571, PMID:31636315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 High

    Establishing the structural identity of GAPR-1 was the first step in defining its biochemical capabilities; the crystal structure placed it in the PR-1/CAP fold and revealed an intrinsic propensity to dimerize.

    Evidence Yeast two-hybrid, X-ray crystallography at 1.55 Å, and site-directed mutagenesis of the dimer interface

    PMID:15123429

    Open questions at the time
    • The functional role of the putative catalytic triad was not demonstrated
    • No physiological binding partner identified at this stage
  2. 2010 Medium

    To understand how a peripheral Golgi protein engages membranes, the lipid-binding determinants were defined, showing electrostatic preference for anionic phospholipids beyond myristoylation alone.

    Evidence Liposome binding assays, gel-shift, and mass spectrometry of bound phosphoinositides

    PMID:20095951

    Open questions at the time
    • Functional consequence of phosphatidic acid preference in cells not established
    • Stoichiometry of PI binding not linked to a downstream activity
  3. 2012 High

    This work connected conformational state to function by showing that an alternative inositol-phosphate-induced dimer drives membrane tethering, establishing dimerization as a regulatory switch for membrane behavior.

    Evidence X-ray crystallography with phytic acid, light scattering, flow cytometry, and conformation-locking mutants (D81K, A68K)

    PMID:22560898

    Open questions at the time
    • Physiological trigger for the alternative dimer in vivo unknown
    • Relationship of tethering to Golgi function not tested
  4. 2006 Medium

    The first cellular role emerged from fibrotic kidney, linking GLIPR2 to epithelial-mesenchymal transition rather than to any structural prediction.

    Evidence Transcript profiling in COL4A3 knockout mice, immunofluorescence, and in vitro EMT assays in renal epithelial cells

    PMID:17055234

    Open questions at the time
    • Molecular pathway driving EMT not defined
    • Causality versus correlation in fibrosis not resolved
  5. 2013 Medium

    Two studies established a mechanistic route for the EMT phenotype, implicating ERK1/2 activation in both renal epithelial and hepatocellular carcinoma contexts under overexpression and hypoxia.

    Evidence Stable overexpression and siRNA knockdown in HK-2, HepG2, and PLC/PRF/5 cells with EMT marker, migration/invasion, and ERK1/2 readouts

    PMID:23516513 PMID:24204846

    Open questions at the time
    • Direct molecular link between GLIPR2 and ERK activation not shown
    • Whether membrane or Golgi localization is required for signaling untested
  6. 2016 Medium

    A distinct immune-signaling function was uncovered by identifying a phosphorylation event and binding partner that modulate TLR4 output.

    Evidence IRAK1 kinase assay identifying Ser58 phosphorylation, co-immunoprecipitation with TMED7, and cytokine/reporter assays

    PMID:26678074

    Open questions at the time
    • Reciprocal validation of the TMED7 interaction limited
    • How phosphorylation alters GLIPR2 conformation or localization unknown
  7. 2017 High

    Structural mapping of a BECN1-binding groove defined the molecular basis for an autophagy-regulatory interaction and tied it to oligomeric state.

    Evidence 1.27 Å crystal structure of a pentad groove mutant, SAXS, pull-downs, and mutagenesis of five conserved groove residues

    PMID:28876241

    Open questions at the time
    • Functional autophagy consequence not yet demonstrated in this study
    • In vivo relevance of dimer-mediated groove occlusion untested
  8. 2020 High

    The autophagy function was causally established by showing GLIPR2 directly inhibits the PtdIns3K-C1 complex, converting the structural BECN1 interaction into a defined negative-regulatory mechanism.

    Evidence CRISPR-Cas9 knockout in HeLa cells and mice, in vitro lipid kinase assays with purified complex, PtdIns3P and WIPI2 readouts

    PMID:33222586

    Open questions at the time
    • Signals that relieve GLIPR2 inhibition of PtdIns3K-C1 unknown
    • Connection between Golgi compaction phenotype and autophagy control unresolved
  9. 2019 High

    Metal-ion biochemistry was dissected to explain the protein's amyloidogenic behavior, defining two mechanistically distinct aggregation pathways governed by zinc versus copper and redox state.

    Evidence ITC, CD, tryptophan fluorescence, ThT/TEM aggregation assays, and His54/His103 and cysteine mutants

    PMID:30700571 PMID:31636315

    Open questions at the time
    • Physiological role of amyloid-like assembly in cells not established
    • Relationship between metal binding and the BECN1/membrane functions unknown
  10. 2021 Medium

    Yeast modeling linked N-myristoylation and metal-binding residues to formation of reversible cytosolic inclusions, connecting the modification and metal chemistry to cellular condensate behavior.

    Evidence Yeast overexpression, fluorescence microscopy with FRAP, mutagenesis, and metal-ion treatment

    PMID:34298062

    Open questions at the time
    • Mammalian relevance of inclusions not shown
    • Functional output of inclusion formation undefined
  11. 2022 Medium

    The BECN1-interaction mechanism was extended to condensate biology, showing GLIPR2 interferes with Beclin 1 condensate formation through the same interface and that B18 amyloidogenic properties matter.

    Evidence Yeast co-expression, fluorescence microscopy, interface mutagenesis, and B18 peptide competition

    PMID:36586462

    Open questions at the time
    • Quantitative impact on autophagy in mammalian cells not measured
    • Whether condensate interference is the in vivo mode of PtdIns3K-C1 inhibition unclear
  12. 2024 Medium

    An upstream regulatory layer was identified, showing SMYD2 methylation stabilizes GLIPR2 against ubiquitination and drives EMT via ERK/p38.

    Evidence Paraquat mouse model, MLE-12 cells, SMYD2 inhibitor AZ505, and GLIPR2 overexpression rescue

    PMID:38879290

    Open questions at the time
    • Methylation site on GLIPR2 not mapped
    • Direct versus indirect SMYD2-GLIPR2 relationship not fully resolved
  13. 2025 Medium

    A vascular role was defined, implicating GLIPR2 in EndoMT and cardiac fibrosis through a PDGFRL/AKT/mTOR axis distinct from its ERK-driven epithelial program.

    Evidence AAV knockdown in AMI mice, gain/loss of function in HCMECs, transcriptome sequencing, and rescue experiments

    PMID:40543810

    Open questions at the time
    • Mechanism by which GLIPR2 engages PDGFRL not defined
    • Reconciliation of ERK versus AKT/mTOR pathways across cell types unknown
  14. 2026 Medium

    The functional necessity of N-myristoylation was extended to ferroptosis, establishing an NMT1/NMT2-GLIPR2 axis as a regulator of ferroptosis sensitivity.

    Evidence Quantitative myristoylproteomics, NMT inhibition, and a G2A myristoylation-deficient rescue assay in NSCLC cells

    PMID:41782991

    Open questions at the time
    • Molecular mechanism by which myristoylated GLIPR2 promotes ferroptosis unknown
    • Link between ferroptotic activity and autophagy/Golgi functions unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLIPR2's distinct activities — PtdIns3K-C1 inhibition, ERK/AKT-driven mesenchymal transitions, TLR4 signaling, pro-ferroptotic activity, and metal-regulated amyloid assembly — are integrated within a single protein, and which are dominant in a given physiological context, remains unresolved.
  • No unifying model linking the structural groove/dimer switch to the diverse signaling outputs
  • Tissue-specific determinants of which pathway dominates are unknown
  • Upstream physiological signals controlling GLIPR2 activity not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BECN1IRAK1SMYD2TMED7

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 GAPR-1 (GLIPR2) forms homodimers both in vitro and in vivo, as determined by yeast two-hybrid screening, biochemical and biophysical assays. The 1.55 Å crystal structure shows GAPR-1 is structurally homologous to PR-1 family members (p14a and Ves V 5). Mutagenesis of conserved residues at the dimer interface leads to a greatly increased dimer population. A potential catalytic triad similar to serine proteases was identified across the dimer interface. Yeast two-hybrid, biochemical/biophysical assays, X-ray crystallography (1.55 Å), site-directed mutagenesis Journal of molecular biology High 15123429
2010 GAPR-1 (GLIPR2) binds negatively charged phospholipid membranes (phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid) via electrostatic interactions; N-terminal myristoylation contributes to but is insufficient for stable membrane anchorage. GAPR-1 shows highest preference for phosphatidic acid. Phosphatidylinositol binds with unusual characteristics — it remains associated after denaturation or organic extraction, and mass spectrometry showed up to 3 PI molecules per GAPR-1 monomer. Liposome binding assay, SDS-PAGE gel-shift, mass spectrometry Molecular membrane biology Medium 20095951
2012 Phytic acid (inositol hexakisphosphate) induces an alternative GAPR-1 dimer conformation distinct from the previously solved dimer (one subunit rotated by 28.5°). In the presence of negatively charged lipids, GAPR-1 causes stable liposome tethering. The [D81K] mutant (stabilizing IP6-induced dimer) also causes tethering, while [A68K] mutant (stabilizing non-rotated dimer) binds but does not tether liposomes, demonstrating that alternative dimerization regulates GAPR-1 membrane interactions. X-ray crystallography, light scattering assay, flow cytometry, site-directed mutagenesis Biochimica et biophysica acta High 22560898
2006 GLIPR-2 protein is upregulated in fibrotic kidney and is expressed in epithelial cells. In vitro experiments showed that GLIPR-2 can induce epithelial-to-mesenchymal transition (EMT) in a renal epithelial cell line. Transcript profiling in COL4A3 knockout mouse, immunofluorescence co-staining, in vitro EMT assay in renal epithelial cells Matrix biology Medium 17055234
2013 GLIPR-2 overexpression in HK-2 proximal renal tubular epithelial cells promotes EMT (decreased E-cadherin, increased vimentin and α-SMA) and cell migration, and activates ERK1/2 signaling; EGFR expression is also elevated in GLIPR-2-overexpressing cells. Stable transfection (pcDNA3.0-GLIPR-2), EMT PCR array, Western blot, cell migration assay PloS one Medium 23516513
2013 Hypoxia upregulates GLIPR-2 expression in hepatocellular carcinoma cells (HepG2 and PLC/PRF/5). GLIPR-2 overexpression promotes migration and invasion via EMT and positively regulates ERK1/2; knockdown of GLIPR-2 attenuates hypoxia-induced migration and invasion. Hypoxia cell culture model, overexpression and siRNA knockdown, migration/invasion assays, Western blot for ERK1/2 PloS one Medium 24204846
2014 GAPR-1 (GLIPR2) forms amyloid-like fibrils in the presence of liposomes containing negatively charged lipids, as shown by electron microscopy, Thioflavin T fluorescence, and circular dichroism. GAPR-1 binds the amyloid-oligomer-specific antibody A11 even without lipids, indicating intrinsic oligomerization tendency. GAPR-1 inhibits Aβ(1-40) aggregation and binds to prefibrillar oligomeric Aβ structures during early fibril formation. Electron microscopy, Thioflavin T fluorescence, circular dichroism, immuno-dot blot with A11 antibody Amyloid Medium 24471790
2016 GAPR-1 (GLIPR2) is phosphorylated at Serine 58 by IRAK1 (the MyD88-dependent TLR4 kinase). This phosphorylation promotes GAPR-1 interaction with TMED7 (a TRAM-TRIF-dependent inhibitor), impairing TMED7-mediated disruption of the TRAM-TRIF complex and thereby enhancing IFN-β and IL-10 secretion downstream of TLR4. Kinase assay (IRAK1-mediated phosphorylation), co-immunoprecipitation, reporter/cytokine assays Inflammation Medium 26678074
2017 GAPR-1 (GLIPR2) binds Beclin 1 residues 267–284 via a conserved equatorial surface groove on GAPR-1. Mutagenesis of five conserved groove-lining residues (H54A/E86A/G102K/H103A/N138G) abrogates Beclin 1 binding. The 1.27 Å crystal structure of the pentad mutant shows the groove is shallower and more positively charged. SAXS analysis reveals that WT GAPR-1 is monomeric in solution while the pentad mutant is primarily dimeric, and dimeric GAPR-1 is unlikely to bind Beclin 1 because the groove is partially occluded. X-ray crystallography (1.27 Å), SAXS, mutagenesis, pull-down assays, structural modeling Acta crystallographica. Section D, Structural biology High 28876241
2019 GAPR-1 (GLIPR2) binds zinc ions (demonstrated by ITC). Zn2+ binding causes a conformational change (shown by CD, tryptophan fluorescence, trypsin digestion) required for oligomerization and amyloid-like assembly in the presence of heparin. Molecular dynamics simulations place Zn2+ binding at His54 and His103; mutation of these residues strongly diminishes amyloid-like aggregation. Isothermal titration calorimetry, circular dichroism, tryptophan fluorescence, trypsin digestion, Thioflavin T fluorescence, TEM, molecular dynamics simulations, site-directed mutagenesis Bioscience reports High 30700571
2019 Copper ions induce a distinct amyloid-like aggregation pathway of GAPR-1 in the presence of heparin, independent of the conserved Zn2+-binding site (His54/His103), involving disulfide bond formation and distinct nucleation/elongation phases. The Zn2+-dependent aggregation pathway is cysteine-independent and reversible upon Zn2+ removal. These two pathways are mechanistically distinct. Thioflavin T fluorescence, TEM, site-directed mutagenesis (cysteine mutants, His54/His103 mutants), redox manipulation Scientific reports Medium 31636315
2020 GLIPR2 is a negative regulator of the PtdIns3K-C1 autophagy complex and basal autophagy. GLIPR2 was identified as binding to BECN1 residues 267–284. CRISPR-Cas9 depletion of GLIPR2 in HeLa cells increased autophagic flux and PtdIns3P generation. Purified GLIPR2 bound to PtdIns3K-C1 and directly inhibited its in vitro lipid kinase activity. GLIPR2 KO in mice increased basal autophagic flux and WIPI2 recruitment. GLIPR2 loss also caused less compact Golgi structure. CRISPR-Cas9 knockout (cells and mice), in vitro lipid kinase assay with purified complex, autophagic flux assays, PtdIns3P detection, WIPI2 immunofluorescence Autophagy High 33222586
2021 N-myristoylation of GAPR-1 is an important determinant of early-stage cytosolic inclusion formation in yeast. Mutations in conserved metal-binding site residues (His54, His103) enhanced inclusion formation, and Zn2+ addition promotes inclusion formation while reducing GAPR-1 degradation, suggesting stabilization in inclusions. Yeast overexpression, fluorescence microscopy, FRAP (dynamic/reversible inclusions), mutagenesis, metal ion treatment Journal of molecular biology Medium 34298062
2022 GAPR-1 (GLIPR2) interferes with Beclin 1 condensate formation in yeast through direct protein–protein interaction at the same binding interface previously characterized in mammalian cells. Mutations of the GAPR-1/Beclin 1 interaction site and the B18 Beclin 1-derived peptide (which binds GAPR-1) abolish the reduction of Beclin 1 condensates. Amyloidogenic properties of the B18 peptide are important for interaction with GAPR-1. Yeast co-expression system, fluorescence microscopy, mutagenesis of interaction surfaces, peptide competition assay Journal of molecular biology Medium 36586462
2024 SMYD2 methylates GLIPR2 to stabilize it; SMYD2 inhibition decreases GLIPR2 methylation and facilitates GLIPR2 ubiquitination, leading to GLIPR2 destabilization. GLIPR2 mediates EMT downstream of SMYD2 through the ERK/p38 pathway; GLIPR2 overexpression rescued the inhibitory effect of SMYD2 inhibition on ERK/p38 and EMT. In vivo PQ-mouse model (western blot, immunofluorescence), in vitro MLE-12 cell model, SMYD2 inhibitor AZ505, GLIPR2 overexpression rescue experiments Pesticide biochemistry and physiology Medium 38879290
2025 GLIPR2 promotes endothelial-to-mesenchymal transition (EndoMT) and cardiac fibrosis after AMI through the PDGFRL/AKT/mTOR signaling pathway. AAV-mediated knockdown of GLIPR2 in mice reversed EndoMT and attenuated cardiac fibrosis. Transcriptome sequencing and rescue experiments identified PDGFRL/AKT/mTOR as the critical downstream pathway. AAV-targeted knockdown in AMI mouse model, lentiviral overexpression/knockdown in HCMECs, transcriptome sequencing, rescue experiments Life sciences Medium 40543810
2026 GLIPR2 is N-myristoylated, and this modification is required for its pro-ferroptotic activity in NSCLC cells. A myristoylation-deficient mutant (G2A) failed to restore ferroptosis sensitivity, establishing that N-myristoylation is functionally necessary for GLIPR2's role in ferroptosis. NMT1/NMT2 inhibition attenuated ferroptosis, and the NMT1/NMT2-GLIPR2 axis was identified as a regulator of ferroptosis. Quantitative myristoylproteomics (click chemistry), genetic/pharmacological NMT inhibition, GLIPR2 overexpression/KD, G2A myristoylation-deficient mutant functional rescue assay Materials today. Bio Medium 41782991

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Identification of distinct populations of prostasomes that differentially express prostate stem cell antigen, annexin A1, and GLIPR2 in humans. Biology of reproduction 192 22133690
2004 Structural analysis of the human Golgi-associated plant pathogenesis related protein GAPR-1 implicates dimerization as a regulatory mechanism. Journal of molecular biology 62 15123429
2020 GLIPR2 is a negative regulator of autophagy and the BECN1-ATG14-containing phosphatidylinositol 3-kinase complex. Autophagy 35 33222586
2017 miR-30e targets GLIPR-2 to modulate diabetic nephropathy: in vitro and in vivo experiments. Journal of molecular endocrinology 33 28733476
2013 GLIPR-2 overexpression in HK-2 cells promotes cell EMT and migration through ERK1/2 activation. PloS one 32 23516513
2012 Interaction of GAPR-1 with lipid bilayers is regulated by alternative homodimerization. Biochimica et biophysica acta 28 22560898
2010 Binding of GAPR-1 to negatively charged phospholipid membranes: unusual binding characteristics to phosphatidylinositol. Molecular membrane biology 27 20095951
2006 The plant pathogenesis related protein GLIPR-2 is highly expressed in fibrotic kidney and promotes epithelial to mesenchymal transition in vitro. Matrix biology : journal of the International Society for Matrix Biology 24 17055234
2014 Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) forms amyloid-like fibrils by interaction with acidic phospholipids and inhibits Aβ aggregation. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 22 24471790
2022 LncRNA NEAT1 Accelerates the Proliferation, Oxidative Stress, Inflammation, and Fibrosis and Suppresses the Apoptosis Through the miR-423-5p/GLIPR2 Axis in Diabetic Nephropathy. Journal of cardiovascular pharmacology 21 34803150
2013 Hypoxia promotes epithelial--mesenchymal transition of hepatocellular carcinoma cells via inducing GLIPR-2 expression. PloS one 21 24204846
2017 Structural insights into the interaction of the conserved mammalian proteins GAPR-1 and Beclin 1, a key autophagy protein. Acta crystallographica. Section D, Structural biology 16 28876241
2016 The Golgi-Associated Plant Pathogenesis-Related Protein GAPR-1 Enhances Type I Interferon Signaling Pathway in Response to Toll-Like Receptor 4. Inflammation 16 26678074
2002 Cloning and characterization of a human novel gene C9orf19 encoding a conserved putative protein with an SCP-like extracellular protein domain. Gene 16 12137952
2019 Zinc binding regulates amyloid-like aggregation of GAPR-1. Bioscience reports 15 30700571
2004 Crystallization of a Golgi-associated PR-1-related protein (GAPR-1) that localizes to lipid-enriched microdomains. Acta crystallographica. Section D, Biological crystallography 10 15039568
2019 Metal ions and redox balance regulate distinct amyloid-like aggregation pathways of GAPR-1. Scientific reports 9 31636315
2024 GLIPR2: a potential biomarker and therapeutic target unveiled - Insights from extensive pan-cancer analyses, with a spotlight on lung adenocarcinoma. Frontiers in immunology 8 38476239
2024 Inhibition of SMYD2 attenuates paraquat-induced pulmonary fibrosis by inhibiting the epithelial-mesenchymal transition through the GLIPR2/ERK/p38 axis. Pesticide biochemistry and physiology 6 38879290
2022 GAPR-1 Interferes with Condensate Formation of Beclin 1 in Saccharomyces cerevisiae. Journal of molecular biology 5 36586462
2021 Dynamic and Reversible Aggregation of the Human CAP Superfamily Member GAPR-1 in Protein Inclusions in Saccharomyces cerevisiae. Journal of molecular biology 3 34298062
2025 GLIPR2 regulates EndoMT and cardiac fibrosis after AMI via PDGFRL/AKT/mTOR signaling pathway. Life sciences 2 40543810
2026 Application of a novel myristoylproteomics approach identifies GLIPR2 as a key pro-ferroptotic substrate in non-small cell lung cancer. Materials today. Bio 1 41782991
2025 Chaize mixture alleviates NAFLD by regulating Glipr2-related autophagy/NLRP3 signaling. International immunopharmacology 1 41045801

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