Affinage

PPT1

Palmitoyl-protein thioesterase 1 · UniProt P50897

Length
306 aa
Mass
34.2 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPT1 is a ubiquitously expressed glycoprotein thioesterase that removes palmitate from S-acylated cysteine residues on proteins undergoing lysosomal degradation, and its loss causes infantile neuronal ceroid lipofuscinosis (INCL/CLN1 disease) (PMID:8786130, PMID:11717424, PMID:12069847). Biochemical fractionation localizes its catalytic action to the lysosome, where it depalmitoylates substrate proteins en route to degradation, while in neurons the enzyme is additionally found at synaptosomes and synaptic vesicles and is routed via the mannose-6-phosphate receptor (PMID:11136716, PMID:12069847). Crystallographic comparison with PPT2 attributes its ability to act on palmitoylated proteins to a solvent-exposed lipid-binding groove (PMID:12855696), and N-glycosylation at N197/N232 plus oligomerization are required for activity and trafficking (PMID:17565660). Catalytic activity is functionally essential, as catalytically dead enzyme fails to reproduce gain-of-function phenotypes (PMID:14629778), and the enzyme is itself palmitoylated at cysteine-6 by DHHC3/DHHC7, which non-competitively inhibits its activity in a feedback loop (PMID:26731412). Identified substrates whose stability and trafficking it controls include CSPα, Rab7, GFAP (at C291), and Gpx1 (at C76/C113) (PMID:26659577, PMID:32279353, PMID:33753498, PMID:39423458). PPT1 deficiency triggers ER stress and the unfolded protein response with downstream caspase activation and neuronal apoptosis, disrupts Rab7-RILP-dependent autophagosome-lysosome fusion, and impairs cathepsin D maturation, collectively driving neurodegeneration (PMID:16368712, PMID:16644870, PMID:32279353, PMID:26160911). Beyond its disease role, PPT1 promotes endosomal acidification via V-ATPase recruitment in dendritic cells (PMID:31262842) and is the direct molecular target of chloroquine-derivative autophagy inhibitors used against cancer (PMID:30442709).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1996 High

    Established the molecular identity of PPT1 as a glycosylated thioesterase that removes palmitate from lipid-modified cysteine residues, defining the enzyme to be characterized.

    Evidence cDNA/genomic cloning, sequence analysis, and Northern blot showing ubiquitous 2.5-kb transcript

    PMID:8786130

    Open questions at the time
    • Physiological substrates not yet identified
    • Subcellular site of action not yet established
  2. 2001 High

    Linked PPT1 loss to a defined neurodegenerative disease, showing the enzyme is deficient in INCL and acts on cysteine-modified proteins undergoing lysosomal degradation.

    Evidence PPT1 knockout mouse with INCL-like neuropathology plus enzymatic assays

    PMID:11717424

    Open questions at the time
    • Specific disease-driving substrates undefined
    • Molecular cascade from enzyme loss to apoptosis unresolved
  3. 2001 High

    Resolved the cell-type-specific routing of PPT1, distinguishing classical M6PR-dependent lysosomal targeting in non-neuronal cells from synaptic localization in neurons.

    Evidence Confocal/cryo-IEM, fractionation, and M6PR binding across neuronal, COS-1, and polarized epithelial cells

    PMID:11136716

    Open questions at the time
    • Mechanism directing neuronal synaptic localization unclear
    • Functional role at synaptic vesicles undefined
  4. 2002 High

    Demonstrated that PPT1 acts within the lysosome to remove fatty acids from proteins during degradation, fixing the site of catalytic action.

    Evidence Biochemical fractionation with [35S]cysteine labeling and lysosomal protease/acidification inhibitors

    PMID:12069847

    Open questions at the time
    • Identity of accumulating thioester substrates not defined
    • Does not address extralysosomal neuronal pools
  5. 2003 High

    Provided the structural basis for PPT1's substrate specificity, explaining why it acts on palmitoylated proteins whereas PPT2 prefers unbranched acyl-CoA.

    Evidence X-ray crystallography of PPT2, structural comparison with PPT1, and in vitro substrate specificity assays

    PMID:12855696

    Open questions at the time
    • No co-crystal with a protein substrate
    • Catalytic mechanism detail on intact proteins untested
  6. 2003 Medium

    Showed that PPT1 function in vivo depends on its catalytic activity, ruling out a purely structural role.

    Evidence Drosophila over-expression of wild-type vs. catalytic-mutant (S123A) DmPpt1 with eye phenotype readout

    PMID:14629778

    Open questions at the time
    • Over-expression phenotype not directly equivalent to loss-of-function disease
    • Mammalian substrate relevance not addressed
  7. 2005 High

    Defined a death pathway downstream of PPT1 loss: ER accumulation of palmitoylated GAP-43 triggers UPR and caspase-mediated neuronal apoptosis.

    Evidence PPT1-KO mouse brain and GFP-GAP-43 expression with UPR/caspase Western blots

    PMID:16368712

    Open questions at the time
    • GAP-43 causal contribution to disease not proven by rescue
    • Other accumulating substrates not enumerated
  8. 2006 High

    Extended the apoptotic mechanism to human INCL and to additional death branches (oxidative/mitochondrial), confirming caspase-driven neurodegeneration.

    Evidence Human INCL cells with caspase-4 inhibition rescue; KO brain/neurosphere ROS, SOD-2, caspase-9/3, PARP measurements

    PMID:16571600 PMID:16644870

    Open questions at the time
    • Relative contribution of ER-stress vs. mitochondrial pathways unquantified
    • Caspase-9 pathway placement by correlation, not rescue
  9. 2006 Medium

    Connected PPT1 loss to broader lysosomal/endocytic dysfunction by showing impaired endocytosis and aberrant prosaposin processing.

    Evidence Endocytosis assays, metabolic labeling/IP of prosaposin, and saposin localization in PPT1-deficient fibroblasts and neurons

    PMID:16542649

    Open questions at the time
    • Direct molecular link between PPT1 activity and endocytic machinery unidentified
    • Single-lab finding
  10. 2007 High

    Defined post-translational and assembly requirements for PPT1, showing N197/N232 glycosylation and oligomerization are needed for activity and trafficking.

    Evidence Site-directed mutagenesis of glycosylation sites, SEC, co-IP, and deglycosylation experiments

    PMID:17565660

    Open questions at the time
    • Structural basis of oligomerization not resolved
    • Why disease mutants hyperglycosylate unclear
  11. 2007 Medium

    Identified a lipid-signaling consequence of PPT1 loss linking enzyme deficiency to phagocyte-driven neuroinflammation via LPC accumulation.

    Evidence Brain lipid analysis, cPLA2 activity, and gene expression correlation in PPT1-KO mice

    PMID:17341491

    Open questions at the time
    • cPLA2 activation mechanism downstream of PPT1 loss undefined
    • Causal role of LPC in pathology shown only by correlation
  12. 2008 Medium

    Reported a non-canonical PPT1 interaction with mitochondrial ATP synthase F1-complex and altered lipoprotein handling, broadening its functional context.

    Evidence Co-purification, in vitro binding, cell-surface biotinylation/TIRF, and ApoA-I uptake assays in Ppt1-deficient mice

    PMID:18245779

    Open questions at the time
    • Functional significance of the F1-complex interaction unresolved
    • Single co-purification without reciprocal validation
  13. 2015 High

    Began identifying specific physiological substrates and processing roles: CSPα as a PPT1 substrate and cathepsin D maturation dependence on PPT1.

    Evidence Co-IP and palmitoylome proteomics from DNAJC5/CLN4 patient brains; cathepsin D maturation Westerns with NtBuHA rescue in Cln1-/- mice

    PMID:26160911 PMID:26659577

    Open questions at the time
    • Mechanism by which PPT1 controls cathepsin D processing indirect
    • Causality between palmitoylome shifts and disease not fully resolved
  14. 2016 High

    Revealed autoregulation: PPT1 is palmitoylated at Cys6 by DHHC3/7, which non-competitively inhibits its activity, establishing a feedback loop controlling global palmitoylation.

    Evidence C6S mutagenesis, in vitro/in vivo palmitoylation assays, DHHC co-expression, and enzyme kinetics

    PMID:26731412

    Open questions at the time
    • Physiological conditions regulating PPT1 palmitoylation unknown
    • Impact on disease progression untested
  15. 2018 High

    Identified PPT1 as the direct molecular target of chloroquine-derivative autophagy inhibitors, repurposing it as an anticancer drug target.

    Evidence In situ photoaffinity pulldown, enzyme inhibition assays, and CRISPR PPT1 knockout with tumor growth assays

    PMID:30442709

    Open questions at the time
    • Binding-site structural detail not resolved
    • Substrate(s) mediating the autophagy-modulating effect undefined
  16. 2019 High

    Defined a cell-type-specific physiological role in dendritic cells, where PPT1 drives V-ATPase-dependent endosomal acidification and antigen degradation, balancing antiviral defense against T cell priming.

    Evidence PPT1-deficient mice, VSV infection, in vivo T cell priming, V-ATPase recruitment, and Listeria clearance assays

    PMID:31262842

    Open questions at the time
    • Direct V-ATPase substrate/palmitoylation link not defined
    • Relationship to neuronal PPT1 function unclear
  17. 2019 Medium

    Placed PPT1 in the broader NCL network by showing CLN3 controls lysosomal PPT1 delivery via CI-M6PR trafficking.

    Evidence Lysosomal fractionation and PPT1 activity in Cln3-mutant mice and JNCL patient cells

    PMID:31025705

    Open questions at the time
    • Direct CLN3-CI-M6PR mechanism not fully resolved
    • Single-lab epistasis
  18. 2020 Medium

    Mechanistically linked PPT1 loss to autophagy failure through defective Rab7 palmitoylation, blocking Rab7-RILP interaction and autophagosome-lysosome fusion.

    Evidence Autophagy flux, Rab7 palmitoylation, Rab7-RILP co-IP, and NtBuHA rescue in Cln1-/- mice and patient fibroblasts

    PMID:32279353

    Open questions at the time
    • Direct demonstration that Rab7 is a PPT1 catalytic substrate incomplete
    • Single-lab finding
  19. 2021 High

    Expanded the substrate repertoire and disease mechanism through GFAP (C291) depalmitoylation controlling astrogliosis, and a microglial ZDHHC/APT1/H-Ras axis driving neuroinflammation.

    Evidence Palmitoylation assays and C291A mutagenesis in PPT1-knockin mice; ZDHHC5/23, APT1 palmitoylation, and H-Ras localization with NtBuHA rescue in Cln1-/- mice

    PMID:33739454 PMID:33753498

    Open questions at the time
    • GFAP/H-Ras contributions to overall disease severity not quantified
    • Microglial axis is single-lab
  20. 2021 Medium

    Characterized the downstream lysosomal consequences of pharmacological PPT1 inhibition in cancer: Zn2+ accumulation, cathepsin impairment, autophagy blockade, and lysosomal membrane permeabilization.

    Evidence GNS561 PPT1 inhibition with lysosomal Zn2+, cathepsin, autophagy flux, mTOR localization, and in vivo HCC assays

    PMID:34740311

    Open questions at the time
    • Direct PPT1 substrate mediating these effects undefined
    • Single-lab finding
  21. 2024 Medium

    Added Gpx1 (C76/C113) as a PPT1 substrate whose depalmitoylation destabilizes the protein and drives neovascular angiogenesis, extending PPT1 function beyond neurodegeneration.

    Evidence Gpx1 palmitoylation-site mapping, PPT1-deficient OIR mouse model, and DC661 inhibition in angiogenesis assays

    PMID:39423458

    Open questions at the time
    • Tissue specificity of Gpx1 regulation unclear
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PPT1 substrate selection is governed in different compartments (lysosome vs. synapse vs. endosome) and which specific depalmitoylation events are causally rate-limiting for INCL and for cancer drug response remain unresolved.
  • No unifying model linking individual substrate effects to disease severity
  • Structural basis of inhibitor and substrate binding incomplete
  • Mechanism of neuronal non-lysosomal targeting unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 4
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 3
Partners
CSPALPHADHHC3DHHC7GFAPGPX1RAB7RILP

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PPT1 (palmitoyl-protein thioesterase) encodes a 306-amino acid glycoprotein with a 25-amino-acid signal peptide, three N-linked glycosylation sites, and consensus motifs characteristic of thioesterases; it removes palmitate groups from cysteine residues in lipid-modified proteins. Northern analysis revealed ubiquitous expression of a single 2.5-kb mRNA. cDNA and genomic cloning, sequence analysis, Northern blot Genomics High 8786130
2001 PPT1 disruption in knockout mice causes infantile neuronal ceroid lipofuscinosis (INCL)-like neurodegeneration with autofluorescent storage material, neuronal apoptosis, spasticity, seizures, and death by 10 months, demonstrating that PPT1 is the enzyme deficient in INCL. PPT1 hydrolyzes fatty acids from modified cysteine residues in proteins undergoing lysosomal degradation, in addition to hydrolyzing long-chain fatty acyl CoAs. Gene knockout mouse model, histopathology, enzymatic assays Proceedings of the National Academy of Sciences of the United States of America High 11717424
2001 In mouse primary neurons and brain tissue, PPT1 localizes to synaptosomes and synaptic vesicles but not to lysosomes, contrasting with its classical lysosomal routing in non-neuronal cells. PPT1 is recognized by the mannose-6-phosphate receptor (M6PR) and routed to lysosomes in COS-1 cells, with a substantial fraction secreted. In polarized epithelial cells, PPT1 localizes exclusively to the basolateral site. Confocal microscopy, cryoimmunoelectron microscopy, cell fractionation, mannose-6-phosphate receptor binding assay Human molecular genetics High 11136716
2003 Structural comparison of PPT1 and PPT2 crystal structures revealed that conformational differences in helix α4 create a solvent-exposed lipid-binding groove in PPT1 that is absent in PPT2, explaining why PPT1 can hydrolyze palmitoylcysteine and palmitoylated proteins while PPT2 preferentially hydrolyzes unbranched substrates like palmitoyl-CoA. Differences in the space between two parallel loops (β3-αA and β8-αF) above the lipid-binding groove account for the divergent substrate specificities. X-ray crystallography (PPT2 at 2.7 Å resolution), structural comparison with PPT1, in vitro substrate specificity assays The Journal of biological chemistry High 12855696
2005 PPT1 deficiency (Ppt1Δex4 knockout mice) causes endoplasmic reticulum stress, activation of the unfolded protein response (UPR) marked by elevated phospho-eIF2α and GRP78, and activation of caspase-12 followed by caspase-3, leading to neuronal apoptosis. The palmitoylated neuronal protein GAP-43 accumulates abnormally in the ER of PPT1-deficient cells. PPT1 knockout mouse brain analysis, forced expression of GFP-GAP-43 in PPT1-deficient cells, Western blot for UPR markers (eIF2α phosphorylation, GRP78, caspase-12 cleavage) Human molecular genetics High 16368712
2006 In human INCL brain (PPT1-deficient), ER stress-induced UPR activates caspase-4 (the human counterpart of murine caspase-12) and caspase-3, leading to apoptosis. GAP-43, a palmitoylated protein, accumulates abnormally in the ER of INCL cells. Inhibition of caspase-4 activity protects INCL cells from apoptosis. Western blot, immunofluorescence in cultured INCL cells, GFP-GAP-43 transfection and localization, caspase-4 inhibitor treatment Human molecular genetics High 16644870
2006 PPT1 deficiency elevates reactive oxygen species (ROS) and superoxide dismutase-2 (SOD-2) levels in INCL brain and neurospheres, leading to calcium homeostasis disruption and caspase-9 activation via mitochondrial membrane destabilization, which then activates caspase-3 and PARP cleavage (apoptosis). Analysis of PPT1-KO mouse brain tissues and cultured neurospheres from PPT1-KO fetuses; measurement of ROS, SOD-2, cleaved caspase-9, caspase-3, PARP Human molecular genetics Medium 16571600
2007 PPT1's N-glycosylation at N197 and N232 (but not N212) is essential for its enzymatic activity and intracellular transport. PPT1 forms oligomeric complexes as demonstrated by size-exclusion chromatography and co-immunoprecipitation. PPT1 processing and trafficking differs between neuronal and non-neuronal cells. Disease-causing mutations increase both the degree of glycosylation of PPT1 and its ability to form complexes. Site-directed mutagenesis of glycosylation sites, size-exclusion chromatography, co-immunoprecipitation, antibody internalization assays, deglycosylation experiments BMC cell biology High 17565660
2007 PPT1 deficiency leads to increased production of lysophosphatidylcholine (LPC), catalyzed by activation of cytosolic phospholipase A2 (cPLA2) in the PPT1-KO mouse brain. Age-dependent increases in LPC levels positively correlate with elevated expression of phagocyte-associated genes, identifying LPC as a 'lipid signal' for phagocyte recruitment contributing to INCL neuropathology. Lipid analysis of PPT1-KO mouse brain, cPLA2 activity assay, gene expression analysis, correlation of LPC levels with phagocyte markers Human molecular genetics Medium 17341491
2008 PPT1 interacts with the F1-complex of mitochondrial ATP synthase (identified by co-purification and in vitro-binding assays). In Ppt1-deficient neurons, the levels of F1-subunits α and β on the plasma membrane are specifically increased. Ppt1-deficiency is also associated with changes in apolipoprotein A-I uptake and altered serum lipid composition. Co-purification, in vitro binding assays, cell surface biotinylation, TIRF-microscopy, apolipoprotein A-I uptake assays in Ppt1Δex4 mice Human molecular genetics Medium 18245779
2006 PPT1 deficiency causes a defect in fluid-phase and receptor-mediated endocytosis (while marker uptake and recycling endocytosis remain intact), leading to hypersecretion and abnormal processing of prosaposin, resulting in accumulation of saposins A and D in PPT1-deficient fibroblasts and neurons. Endocytosis assays, metabolic labeling and immunoprecipitation of prosaposin, saposin localization by immunofluorescence in PPT1-deficient fibroblasts and mouse primary neurons Experimental cell research Medium 16542649
2015 CSPα (encoded by DNAJC5/CLN4) is a substrate of PPT1; PPT1 depalmitoylates CSPα. In DNAJC5/CLN4 patient brains, PPT1 protein is massively increased but its specific enzymatic activity is dramatically reduced and it is mis-localized. Global changes in protein palmitoylation (primarily lysosomal and synaptic proteins) occur as a consequence of PPT1 accumulation without sufficient activity. Co-immunoprecipitation, quantitative palmitoylome proteomics from patient brains, enzymatic activity assays Acta neuropathologica High 26659577
2016 PPT1 itself undergoes palmitoylation in vivo at cysteine-6, catalyzed by DHHC3 and DHHC7. Palmitoylation of PPT1 inhibits its depalmitoylation enzymatic activity (acts as a non-competitive inhibitor affecting Vmax) without affecting intracellular localization. The unpalmitoylated C6S mutant shows enhanced depalmitoylation activity, establishing a positive feedback loop where palmitoylation of PPT1 reduces its activity and increases substrate palmitoylation. Site-directed mutagenesis (C6S), in vitro and in vivo palmitoylation assays, DHHC enzyme co-expression, enzymatic kinetics (Vmax measurement), subcellular localization PloS one High 26731412
2018 PPT1 is the molecular target of chloroquine (CQ) derivatives including hydroxychloroquine (HCQ), Lys05, and dimeric CQ (DC661). Using photoaffinity pulldown, CQ derivatives were shown to bind and inhibit PPT1 enzymatic activity. CRISPR/Cas9 knockout of PPT1 in cancer cells abrogates autophagy modulation and cytotoxicity of CQ derivatives and significantly impairs tumor growth. In situ photoaffinity pulldown, enzymatic activity assays, CRISPR/Cas9 PPT1 knockout in cancer cells, tumor growth assays Cancer discovery High 30442709
2019 PPT1 is highly expressed in conventional type 1 dendritic cells (cDC1s) and promotes antigen degradation and endosomal acidification via V-ATPase recruitment, protecting DCs from viral infection. PPT1-deficient cDC1s show impaired response to VSV infection but enhanced priming of naive CD8+ T cells into KLRG1+ effectors and memory T cells. After DC activation, PPT1 is rapidly downregulated to facilitate cross-presentation. PPT1-deficient mouse models, VSV infection assays, T cell priming assays (in vivo), V-ATPase recruitment measurement, Listeria monocytogenes clearance assay The Journal of experimental medicine High 31262842
2020 PPT1 deficiency in Cln1-/- mice disrupts Rab7 S-palmitoylation-dependent trafficking to late endosomal/lysosomal membranes, preventing Rab7-RILP interaction and autophagosome-lysosome fusion, thereby impairing autophagic degradation. Treatment with NtBuHA (a PPT1-mimetic) ameliorated this defect. Autophagy flux assays in Cln1-/- mice and INCL patient fibroblasts, Rab7 palmitoylation assays, Rab7-RILP co-immunoprecipitation, NtBuHA rescue experiments Journal of inherited metabolic disease Medium 32279353
2021 PPT1 depalmitoylates GFAP at cysteine-291, which is the unique palmitoylation site of GFAP. In PPT1-knockin mice, hyperpalmitoylated GFAP promotes astrocyte proliferation and astrogliosis. Blocking GFAP palmitoylation by mutating C291 to alanine attenuates astrogliosis and neurodegenerative pathology in PPT1-knockin mice. In vitro and in vivo palmitoylation assays, site-directed mutagenesis (C291A), astrocyte proliferation assays, histopathology of PPT1-KI mice Proceedings of the National Academy of Sciences of the United States of America High 33753498
2021 PPT1 inhibition by GNS561 results in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered localization of mTOR, lysosomal membrane permeabilization, and caspase activation in hepatocellular carcinoma cells. PPT1 enzymatic activity assays, lysosomal Zn2+ measurement, cathepsin activity assays, autophagy flux assays, mTOR localization by immunofluorescence, in vivo HCC models Autophagy Medium 34740311
2021 In Cln1-/- mice (INCL model), PPT1-deficiency reduces ZDHHC5 and ZDHHC23 levels, which suppresses APT1 S-palmitoylation, causing increased membrane-localized H-Ras and activation of its proliferative signaling pathway in microglia, contributing to neuroinflammation. Western blot for ZDHHC5/ZDHHC23, APT1 palmitoylation assays, H-Ras membrane localization in Cln1-/- mouse brain, NtBuHA rescue treatment Journal of inherited metabolic disease Medium 33739454
2024 PPT1 mediates depalmitoylation of Gpx1 at cysteine-76 and cysteine-113, thereby negatively regulating Gpx1 protein stability. PPT1-regulated Gpx1 depalmitoylation promotes neovascular angiogenesis; in PPT1-deficient mice, angiogenesis is attenuated in the OIR model, and PPT1 inhibition with DC661 suppresses retinal angiogenesis. Palmitoylation assays (Gpx1 palmitoylation site mapping by mutagenesis), PPT1-deficient mouse OIR model, angiogenesis assays, DC661 pharmacological inhibition Redox biology Medium 39423458
2002 Lipid-cysteine thioesters (substrates for PPT1) accumulate in the lysosomal fraction of PPT1-deficient cells, and their appearance is blocked by inhibitors of lysosomal proteolysis (leupeptin, chloroquine). These substrates also accumulate in normal cells after leupeptin or chloroquine treatment, demonstrating through biochemical fractionation that PPT1 acts in the lysosome to remove fatty acids from proteins undergoing lysosomal degradation. Biochemical cell fractionation, [35S]cysteine metabolic labeling, lysosomal inhibitor treatment (leupeptin, chloroquine, cysteamine), organic phase extraction and analysis Biochimica et biophysica acta High 12069847
2003 Over-expression of DmPpt1 (Drosophila Ppt1 ortholog) in the developing visual system leads to cell loss through apoptotic cell death. Over-expression of the catalytic site mutant DmPpt1-S123A does not cause the eye phenotype, demonstrating that cell loss depends on the catalytic activity of PPT1. Drosophila transgenic over-expression system, active-site serine-to-alanine mutagenesis (S123A), eye morphology phenotype analysis, genetic deficiency suppression BMC neuroscience Medium 14629778
2019 CLN3 mutations suppress the exit of cation-independent mannose-6-phosphate receptor (CI-M6PR) from the trans-Golgi network, reducing lysosomal PPT1 protein levels and PPT1 enzymatic activity in Cln3-mutant mice and JNCL patient cells. This establishes a pathway linking CLN3 function to lysosomal PPT1 delivery via CI-M6PR trafficking. Lysosomal fractionation and PPT1 enzymatic activity measurement in Cln3 mutant mice and JNCL patient fibroblasts, V0a1 v-ATPase subunit localization Journal of inherited metabolic disease Medium 31025705
2015 PPT1 deficiency in Cln1-/- mice impairs the proteolytic processing of cathepsin D (CLN10/CD) precursor to its enzymatically active form in the lysosome, despite Cln10 overexpression, thereby impairing lysosomal degradative function. Treatment with NtBuHA ameliorated the cathepsin D processing defect. Western blot for cathepsin D maturation in Cln1-/- mouse brain and cultured brain cells, enzymatic activity assays, confocal microscopy, NtBuHA rescue treatment Human molecular genetics Medium 26160911

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. The EMBO journal 429 8387915
2003 The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation. Mechanisms of development 262 12676324
2001 Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Proceedings of the National Academy of Sciences of the United States of America 257 11717424
2018 PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer. Cancer discovery 202 30442709
1991 FUS3 represses CLN1 and CLN2 and in concert with KSS1 promotes signal transduction. Proceedings of the National Academy of Sciences of the United States of America 192 1946350
1993 Yeast G1 cyclins CLN1 and CLN2 and a GAP-like protein have a role in bud formation. The EMBO journal 151 8262070
1992 SIT4 protein phosphatase is required for the normal accumulation of SWI4, CLN1, CLN2, and HCS26 RNAs during late G1. Genes & development 135 1334024
2006 The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. The EMBO journal 128 16407978
2006 Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. Human molecular genetics 127 16644870
1997 Rad53-dependent phosphorylation of Swi6 and down-regulation of CLN1 and CLN2 transcription occur in response to DNA damage in Saccharomyces cerevisiae. Genes & development 125 9367985
1998 Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Human molecular genetics 113 9425237
1999 A rapid fluorogenic palmitoyl-protein thioesterase assay: pre- and postnatal diagnosis of INCL. Molecular genetics and metabolism 108 10191108
1994 G1 cyclins CLN1 and CLN2 repress the mating factor response pathway at Start in the yeast cell cycle. Genes & development 107 7926787
1998 Class 1 integron-borne multiple-antibiotic resistance carried by IncFI and IncL/M plasmids in Salmonella enterica serotype typhimurium. Antimicrobial agents and chemotherapy 106 9835490
2005 Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Human molecular genetics 101 16368712
2001 Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). Human molecular genetics 97 11136716
2021 GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions. Autophagy 82 34740311
2019 Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer. Journal of experimental & clinical cancer research : CR 78 30876460
2020 PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma. JCI insight 75 32780726
2015 Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta neuropathologica 69 26659577
2013 Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. Nature neuroscience 68 24056696
2005 Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. Neurobiology of disease 66 15649713
1995 Overexpression of SIS2, which contains an extremely acidic region, increases the expression of SWI4, CLN1 and CLN2 in sit4 mutants. Genetics 66 7705654
2020 Highly efficient gene transfer in the mouse gut microbiota is enabled by the Incl2 conjugative plasmid TP114. Communications biology 62 32963323
2010 A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Molecular genetics and metabolism 60 20494602
2007 PPT-DB: the protein property prediction and testing database. Nucleic acids research 58 17916570
2014 IS1R-mediated plasticity of IncL/M plasmids leads to the insertion of bla OXA-48 into the Escherichia coli Chromosome. Antimicrobial agents and chemotherapy 57 24752261
2008 Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism. Human molecular genetics 57 18245779
2017 Synergistic effects of treating the spinal cord and brain in CLN1 disease. Proceedings of the National Academy of Sciences of the United States of America 55 28673981
2009 Divergent effects of estradiol and the estrogen receptor-alpha agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice. Brain research 53 19281799
2006 Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL. Human molecular genetics 53 16571600
2003 The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2. The Journal of biological chemistry 50 12855696
1999 Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Human mutation 50 10477428
2014 The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Human molecular genetics 48 25205113
1998 Potential regulation of Ste20 function by the Cln1-Cdc28 and Cln2-Cdc28 cyclin-dependent protein kinases. The Journal of biological chemistry 48 9737966
2021 GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 47 33753498
2011 Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. Molecular genetics and metabolism 47 21704547
1995 Plus-strand DNA synthesis of the yeast retrotransposon Ty1 is initiated at two sites, PPT1 next to the 3' LTR and PPT2 within the pol gene. PPT1 is sufficient for Ty1 transposition. Journal of molecular biology 47 7563090
1997 Cell cycle-dependent transcription of CLN1 involves swi4 binding to MCB-like elements. The Journal of biological chemistry 45 9083033
2023 Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma. Journal for immunotherapy of cancer 44 37385725
1998 Regulation of cell size by glucose is exerted via repression of the CLN1 promoter. Molecular and cellular biology 44 9566870
2019 Pathogenicity of Clinical OXA-48 Isolates and Impact of the OXA-48 IncL Plasmid on Virulence and Bacterial Fitness. Frontiers in microbiology 42 31736929
2000 CLN1 and its repression by Xbp1 are important for efficient sporulation in budding yeast. Molecular and cellular biology 42 10611226
2010 Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Human molecular genetics 41 21224254
2019 CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease). Scientific reports 40 31289301
2012 Combination small molecule PPT1 mimetic and CNS-directed gene therapy as a treatment for infantile neuronal ceroid lipofuscinosis. Journal of inherited metabolic disease 40 22310926
2010 Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1. Neuroscience letters 40 20561933
2000 Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells. Journal of neuroscience research 40 11020216
2007 Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction. Neurobiology of disease 39 17656100
2009 Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis. Molecular genetics and metabolism 38 20036592
2007 Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. Human molecular genetics 38 17341491
2013 Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease). Biochimica et biophysica acta 36 23747979
2019 Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells. The Journal of experimental medicine 35 31262842
2007 Glycosylation, transport, and complex formation of palmitoyl protein thioesterase 1 (PPT1)--distinct characteristics in neurons. BMC cell biology 34 17565660
2010 Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. Biochemical and biophysical research communications 33 20346914
2003 An over-expression system for characterizing Ppt1 function in Drosophila. BMC neuroscience 33 14629778
2016 Reversible Cysteine Acylation Regulates the Activity of Human Palmitoyl-Protein Thioesterase 1 (PPT1). PloS one 32 26731412
1997 Deregulation of CLN1 and CLN2 in the Saccharomyces cerevisiae whi2 mutant. Yeast (Chichester, England) 32 9219335
2015 Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules. Neuromolecular medicine 31 26707855
2006 Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. Experimental cell research 31 16542649
2002 Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2). Current molecular medicine 31 12125808
1995 Identification of YAC clones for human chromosome 1p32 and physical mapping of the infantile neuronal ceroid lipofuscinosis (INCL) locus. Genomics 31 7789974
2021 Management of CLN1 Disease: International Clinical Consensus. Pediatric neurology 30 34000449
2008 Ccr4 alters cell size in yeast by modulating the timing of CLN1 and CLN2 expression. Genetics 30 18493058
2022 First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers. Liver cancer 28 35949290
2021 The Cyclin Cln1 Controls Polyploid Titan Cell Formation following a Stress-Induced G2 Arrest in Cryptococcus. mBio 28 34634930
2018 Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses. Orphanet journal of rare diseases 28 29631617
2016 Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis. Journal of veterinary internal medicine 28 28008682
2015 Orexin Receptor Activation Generates Gamma Band Input to Cholinergic and Serotonergic Arousal System Neurons and Drives an Intrinsic Ca(2+)-Dependent Resonance in LDT and PPT Cholinergic Neurons. Frontiers in neurology 28 26082752
2019 InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis. European journal of medicinal chemistry 27 31035240
1996 cDNA and genomic cloning of human palmitoyl-protein thioesterase (PPT), the enzyme defective in infantile neuronal ceroid lipofuscinosis. Genomics 27 8786130
1995 The replication of an IncL/M plasmid is subject to antisense control. Journal of bacteriology 27 7543895
2021 PPT1 Reduction Contributes to Erianin-Induced Growth Inhibition in Oral Squamous Carcinoma Cells. Frontiers in cell and developmental biology 26 35004674
2018 Astrocyte-targeted IL-10 production decreases proliferation and induces a downregulation of activated microglia/macrophages after PPT. Glia 26 30548340
2014 Expanding access to HIV viral load testing: a systematic review of RNA stability in EDTA tubes and PPT beyond current time and temperature thresholds. PloS one 26 25437009
1999 A new simple enzyme assay for pre- and postnatal diagnosis of infantile neuronal ceroid lipofuscinosis (INCL) and its variants. Journal of medical genetics 25 10874636
2022 Mutations in the 3'-PPT Lead to HIV-1 Replication without Integration. Journal of virology 24 35758669
2021 In a mouse model of INCL reduced S-palmitoylation of cytosolic thioesterase APT1 contributes to microglia proliferation and neuroinflammation. Journal of inherited metabolic disease 24 33739454
2020 Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice. Journal of neuroinflammation 24 33115477
2000 Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1, CLN2, and CLN3: functional implications for CLN3. Molecular genetics and metabolism 24 11001812
2014 Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype. Annals of clinical and translational neurology 23 25574475
2015 Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders. Human molecular genetics 22 26160911
2015 Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. Journal of cellular and molecular medicine 22 26648046
2012 Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice. Disease models & mechanisms 22 23065637
2002 The effects of lysosomotropic agents on normal and INCL cells provide further evidence for the lysosomal nature of palmitoyl-protein thioesterase function. Biochimica et biophysica acta 22 12069847
1991 DNA-based prenatal diagnosis of the infantile form of neuronal ceroid lipofuscinosis (INCL, CLN1). Prenatal diagnosis 22 1680233
2022 Seizures in PPT1 Knock-In Mice Are Associated with Inflammatory Activation of Microglia. International journal of molecular sciences 21 35628400
2020 Quantitative γ-H2AX immunofluorescence method for DNA double-strand break analysis in testis and liver after intravenous administration of 111InCl3. EJNMMI research 21 32189079
2020 Spinal manifestations of CLN1 disease start during the early postnatal period. Neuropathology and applied neurobiology 21 32841420
2024 Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1. Redox biology 20 39423458
2009 An integrated strategy for the diagnosis of neuronal ceroid lipofuscinosis types 1 (CLN1) and 2 (CLN2) in eleven Latin American patients. Clinical genetics 20 19793312
2020 Cln1-mutations suppress Rab7-RILP interaction and impair autophagy contributing to neuropathology in a mouse model of infantile neuronal ceroid lipofuscinosis. Journal of inherited metabolic disease 19 32279353
2019 Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype. Scientific reports 19 31578378
2015 Role of Cln1 during melanization of Cryptococcus neoformans. Frontiers in microbiology 19 26322026
2001 Pre- and postnatal enzyme analysis for infantile, late infantile and adult neuronal ceroid lipofuscinosis (CLN1 and CLN2). European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 19 11588995
2000 Identification of three novel mutations of the palmitoyl-protein thioesterase-1 (PPT1) gene in children with neuronal ceroid-lipofuscinosis. Human mutation 19 10649502
1997 ppt-1, a Neurospora crassa PPT/PP5 subfamily serine/threonine protein phosphatase. Biochimica et biophysica acta 19 9256060
1994 Three independent forms of regulation affect expression of HO, CLN1 and CLN2 during the cell cycle of Saccharomyces cerevisiae. Genetics 19 7896087
2019 Cln3-mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl-protein thioesterases-1 (Ppt1)-protein and Ppt1-enzyme activity in the lysosome. Journal of inherited metabolic disease 18 31025705
2018 Urine Multi-drug Screening with GC-MS or LC-MS-MS Using SALLE-hybrid PPT/SPE. Journal of analytical toxicology 18 29762685

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