CTSA encodes cathepsin A, a lysosomal serine carboxypeptidase and protective component of complexes containing neuraminidase NEU1 and beta-galactosidase GLB1. It removes C-terminal amino acids from peptides and also hydrolyzes terminal amides of selected tachykinins, whereas its nonproteolytic association stabilizes lysosomal glycosidases and activates NEU1. The precursor enters the secretory pathway and is processed into disulfide-linked heavy and light chains. CTSA also controls LAMP2A turnover and chaperone-mediated autophagy through proteolysis at the luminal face of the lysosomal membrane. CTSA deficiency causes galactosialidosis, with combined impairment of lysosomal glycosidase activities.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004180 carboxypeptidase activity | IDA PMID:1756715 A mutation in a mild form of galactosialidosis impairs dimer... | MODIFY | Summary: The broad catalytic annotation can be refined to serine-type carboxypeptidase activity. Reason: The human Hu54 construct and its F412V mutant were tested in COS-1 cells using Z-Phe-Ala hydrolysis; the wild-type protein increases activity while the mutant does not. The recovered author thesis includes the original experiment and localization results. Refine the broad carboxypeptidase term to the serine-type mechanism independently established by active-site mutagenesis in PMID:1907282. Proposed replacements: serine-type carboxypeptidase activity Supporting Evidence: PMID:1756715 a mutant protein that lacks cathepsin A-like activity |
| GO:0004180 carboxypeptidase activity | TAS PMID:2244901 Galactosialidosis: simultaneous deficiency of esterase, carb... | MODIFY | Summary: The established carboxypeptidase activity has a more informative serine-type mechanism. Reason: The complete original abstract reports markedly deficient acid carboxypeptidase activity in seven galactosialidosis fibroblast strains. The original full article remained unavailable after attempted original recovery; no uninspected substrate or construct detail is asserted. The broader positive TAS is supported, and serine-type carboxypeptidase is a more informative mechanism established independently in the recovered PMID:1907282 original. Proposed replacements: serine-type carboxypeptidase activity Supporting Evidence: PMID:2244901 carboxypeptidase activity at pH 5.7 were markedly low or deficient |
| GO:0004185 serine-type carboxypeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic inference of serine-type carboxypeptidase activity is supported. Reason: The actual PTHR11802 tree places human CTSA below the GO:0004185 IBD at PTN000210642. The target alignment reproduces the official 480-residue sequence, and neither family loss record lies on its path. The complete literal IBD donor set matches the source assertion; target self-evidence is legitimate. Direct human active-site experiments independently establish the activity. One current fungal donor annotation has a bibliographic mismatch, documented in the source index, which does not invalidate the target activity or the on-path ancestral placement. |
| GO:0004185 serine-type carboxypeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined domain and EC mapping identifies CTSA serine carboxypeptidase activity. Reason: The current official record contains IPR001563, the serine-carboxypeptidase active-site signature IPR018202, IPR033124 and EC 3.4.16.5. These exact source mappings agree with the human catalytic-mutant evidence; this is not an activity inferred from a generic hydrolase fold alone. |
| GO:0004185 serine-type carboxypeptidase activity | IMP PMID:12505983 Cathepsin A regulates chaperone-mediated autophagy through c... | ACCEPT | Summary: Human CTSA has serine-dependent protease activity. Reason: The cited study uses human protective protein and the catalytic Ser150 mutant in mature-chain numbering. It measures carboxypeptidase activity during rescue and separates this from protection of glycosidases. Its additional LAMP2A-cleavage experiments concern an internal cleavage, which should not be represented as proof that all CTSA proteolysis is a C-terminal reaction. |
| GO:0004185 serine-type carboxypeptidase activity | IMP PMID:1907282 Human lysosomal protective protein has cathepsin A-like acti... | ACCEPT | Summary: Active-site mutagenesis establishes serine-type carboxypeptidase activity. Reason: The complete recovered original main text directly tests human protective-protein cDNA, active-site Ser150 and His429 substitutions in mature-chain numbering, synthetic dipeptide hydrolysis and serine-protease inhibitor labeling. Both active-site mutants lose carboxypeptidase activity while retaining trafficking and protection of the glycosidases. These positions correspond to canonical precursor Ser178 and His457. The study establishes the serine-carboxypeptidase activity independently of the protective function. Supporting Evidence: |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: CTSA can occur in the extracellular region after granule release. Reason: The exact Reactome event contains both CTSA processed chains as azurophil-granule cargo and maps their output entities to the extracellular region. This supports a nonexclusive extracellular pool, rather than a claim that CTSA itself drives exocytosis. Its predominant lysosomal enzymatic roles remain distinct. Supporting Evidence: Reactome:R-HSA-6798751 |
| GO:0005764 lysosome | IDA PMID:1756715 A mutation in a mild form of galactosialidosis impairs dimer... | ACCEPT | Summary: Human CTSA is delivered to lysosomes. Reason: The recovered original author chapter describes immunoelectron microscopy of human wild-type and F412V protective protein expressed in COS-1 cells. Wild-type protein labels lysosomes; the mutant has much lower lysosomal labeling and partial ER retention. This directly supports the existing human gene-product localization in a heterologous host. No endogenous human-cell experiment or equivalence of both splice products is inferred. Supporting Evidence: |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: The curated lysosome mapping agrees with direct localization. Reason: UniProt location SL-0158 maps to the lysosome term. Original immunoelectron microscopy of the human protein and precursor processing experiments corroborate that location; this electronic source is retained alongside the separate experimental assertions. |
| GO:0005764 lysosome | NAS PMID:3136930 Expression of cDNA encoding the human "protective protein" a... | ACCEPT | Summary: The human precursor is taken up and processed in the lysosomal pathway. Reason: The recovered original Cell chapter identifies human Hu54 cDNA, its secreted precursor and uptake/processing by human galactosialidosis fibroblasts, with restoration of lysosomal glycosidase activities. Retain the source-specific NAS localization, also directly corroborated by PMID:1756715 and PMID:1907282. The original numbering distinguishes the 28-residue signal peptide from the 452-residue post-signal precursor; it does not describe a third splice product. |
| GO:0005783 endoplasmic reticulum | TAS PMID:1387645 Human lysosomal protective protein. Glycosylation, intracell... | KEEP AS NON CORE | Summary: CTSA precursor is present in the endoplasmic reticulum. Reason: The original human CTSA and GLB1 cotransfection study localizes newly synthesized precursor to the ER and observes their association there. Mutant ER accumulation is distinguished from normal precursor transit. This positive biosynthetic compartment is retained as non-core to the mature lysosomal activities; no splice-product-specific localization is inferred. Supporting Evidence: PMID:1387645 assemble already as precursors |
| GO:0006508 proteolysis | IDA PMID:12505983 Cathepsin A regulates chaperone-mediated autophagy through c... | ACCEPT | Summary: CTSA performs proteolysis of LAMP2A in the cited experiments. Reason: Human PPCA cleaves purified mouse LAMP2A in the reconstitution, with protease inhibition and a cleavage-site substitution supporting specificity. Human galactosialidosis-cell rescue and mouse knockout comparisons connect CTSA proteolysis to receptor turnover. The original preparation contains precursor and mature forms; this is not an assay assigning identical activity to both official splice products. Supporting Evidence: |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: The peptidase family mapping is consistent with directly demonstrated proteolysis. Reason: The target has the exact IPR001563 peptidase S10 family source, and direct human catalytic experiments establish peptide hydrolysis. The electronic proteolysis assertion is retained at its existing broad scope. |
| GO:0006886 intracellular protein transport | TAS PMID:1387645 Human lysosomal protective protein. Glycosylation, intracell... | KEEP AS NON CORE | Summary: CTSA participates in intracellular glycosidase routing through precursor complex assembly. Reason: Human CTSA and GLB1 precursors associate in the ER. ER-retained CTSA mutants co-retain GLB1 and impair its routing, whereas wild-type cotransfection permits delivery and maturation. The contextual transport contribution involves precursor complex assembly, not merely CTSA being cargo, and is retained as non-core to the mature lysosomal activities. GLB1 can reach lysosomes without CTSA, with altered processing; CTSA is not established as an obligatory transport receptor. Supporting Evidence: PMID:1387645 thereby preventing their normal routing |
| GO:0008047 enzyme activator activity | IDA PMID:37205763 Structure of the immunoregulatory sialidase NEU1. | ACCEPT | Summary: CTSA directly activates human NEU1 without supplying sialidase catalysis. Reason: The original Methods and Results directly measure purified human NEU1 activation by purified human CTSA expressed in Sf9 cells. CTSA association increases hydrolysis of 4MU-NANA without assigning sialidase catalysis to CTSA. The proposed NEU1 loop rearrangement remains a model requiring structural confirmation; direct activation is experimentally established. Current GO:0008047 specifically permits noncovalent direct enzyme activation and no inspected descendant supplies a justified NEU1-specific refinement. Supporting Evidence: PMID:37205763 CTSA itself does not hydrolyze 4MU-NANA. |
| GO:0008047 enzyme activator activity | TAS PMID:3107551 Galactosialidosis: a direct evidence that a 46-kilodalton pr... | ACCEPT | Summary: The protective protein restores deficient lysosomal glycosidase activities. Reason: The complete abstract reports that a secreted protective protein restores beta-galactosidase and neuraminidase activities after uptake by galactosialidosis fibroblasts; differential antiserum inhibition distinguishes it from mature beta-galactosidase. Full original Methods remained unavailable after attempted original recovery. Retain this positive historical TAS with its access limitation, independently corroborated by the recovered catalytic-mutant rescue study and purified human NEU1 activation experiment. The abstract does not establish the later molecular activation mechanism by itself. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | UNDECIDED | Summary: The precise CTSA target evidence in the NK-cell membrane proteome remains unverified. Reason: The study isolates membrane fractions from the human YTS NK-cell line, but the available abstract does not identify the CTSA peptide entry and the target-specific supplemental record was not recovered. The HDA assertion is preserved as uncertain. CTSA association with the lysosomal membrane in other experiments does not by itself verify this particular screen, and a soluble precursor does not exclude peripheral membrane association. Supporting Evidence: |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000117 | ACCEPT | Summary: CTSA regulates protein stability through both protective and proteolytic mechanisms. Reason: The current ARBA00033870 rule matches the target FunFam branch. Biological support is independent: CTSA protects lysosomal glycosidases, whereas its catalytic activity promotes LAMP2A turnover. The broad stability term accommodates these distinct substrate-specific directions without attributing glycosidase catalysis to CTSA. |
| GO:0031647 regulation of protein stability | IMP PMID:12505983 Cathepsin A regulates chaperone-mediated autophagy through c... | ACCEPT | Summary: CTSA affects LAMP2A stability through performed proteolysis. Reason: In the cited study, PPCA loss slows LAMP2A degradation, and restoration of protease activity increases receptor turnover. Purified-substrate cleavage and the cleavage-resistant substitution support a performed catalytic contribution, rather than a stability inference from deficiency alone. Supporting Evidence: |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: CTSA processed chains are represented in azurophil-granule lumen cargo. Reason: The actual Reactome input set contains the P10619 heavy and light chains in azurophil-granule lumen. This specialized secretory-granule pool is compatible with CTSA lysosomal localization. The source supports compartment membership and does not imply that CTSA is an exocytosis machinery component. Supporting Evidence: Reactome:R-HSA-6798751 |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605724 | ACCEPT | Summary: CTSA is a lysosomal-lumen component of the modeled glycosidase complex. Reason: The exact Reactome NEU1/NEU4 reaction set resolves through its physical-entity components to the two P10619 processed chains in lysosomal lumen. The model places CTSA in this complex, while NEU1 or NEU4 supplies the sialidase reaction. Independent experiments establish CTSA-mediated NEU1 activation and GLB1 protection; they do not demonstrate NEU4 activation. The chain coordinates refer to the 480-residue precursor and do not establish activity equivalence of the shorter splice product. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-4084999 | ACCEPT | Summary: CTSA is a lysosomal-lumen component of the modeled glycosidase complex. Reason: The exact Reactome NEU1 complex resolves through its physical-entity components to the two P10619 processed chains in lysosomal lumen. The model places CTSA in this complex, while NEU1 or NEU4 supplies the sialidase reaction. Independent experiments establish CTSA-mediated NEU1 activation and GLB1 protection; they do not demonstrate NEU4 activation. The chain coordinates refer to the 480-residue precursor and do not establish activity equivalence of the shorter splice product. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-4341669 | ACCEPT | Summary: CTSA is a lysosomal-lumen component of the modeled glycosidase complex. Reason: The exact Reactome mutant-NEU1 disease complex resolves through its physical-entity components to the two P10619 processed chains in lysosomal lumen. The model places CTSA in this complex, while NEU1 or NEU4 supplies the sialidase reaction. Independent experiments establish CTSA-mediated NEU1 activation and GLB1 protection; they do not demonstrate NEU4 activation. The chain coordinates refer to the 480-residue precursor and do not establish activity equivalence of the shorter splice product. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-9638120 | ACCEPT | Summary: CTSA is a lysosomal-lumen component of the modeled glycosidase complex. Reason: The exact Reactome NEU4 complex resolves through its physical-entity components to the two P10619 processed chains in lysosomal lumen. The model places CTSA in this complex, while NEU1 or NEU4 supplies the sialidase reaction. Independent experiments establish CTSA-mediated NEU1 activation and GLB1 protection; they do not demonstrate NEU4 activation. The chain coordinates refer to the 480-residue precursor and do not establish activity equivalence of the shorter splice product. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: CTSA is detected in the human urinary-exosome proteome. Reason: The authors' urinary-exosome database contains CTSA/NP_000299 with three peptides and an explicit reference to this study. This verifies the target entry and supports a contextual extracellular-vesicle pool. It does not establish exosome biogenesis, a prostate-specific origin, or a particular CTSA splice product. Supporting Evidence: |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | UNDECIDED | Summary: The CTSA-specific entry in the expressed-prostatic-secretion exosome study remains unverified. Reason: The original main text describes exosome-enriched human urine pools, mass-spectrometry identification and potential contamination limits. Its Supplementary Table 2 could not be recovered as a valid workbook, so the target peptide record is not independently verified. The separate positive urinary-exosome dataset is compatible with this annotation but does not substitute for the cited screen. No absence of CTSA from exosomes is inferred. Supporting Evidence: |
| GO:0098575 lumenal side of lysosomal membrane | TAS PMID:20176123 Chaperone-mediated autophagy: molecular mechanisms and physi... | KEEP AS NON CORE | Summary: A CTSA pool associates with the luminal side of the lysosomal membrane. Reason: The cited CMA review describes the peripheral luminal association of cathepsin A during LAMP2A turnover. The original study separates the major soluble lysosomal pool from a smaller membrane-associated pool. Retain this specific regulatory location without making CTSA a transmembrane protein or confining all enzyme activity to the membrane. |
| GO:1904714 regulation of chaperone-mediated autophagy | TAS PMID:20176123 Chaperone-mediated autophagy: molecular mechanisms and physi... | MODIFY | Summary: The cited CMA regulation has a demonstrated negative direction. Reason: The review attributes reduced CMA to cathepsin-A-dependent LAMP2A turnover, which lowers the receptor available for substrate translocation. The original loss, rescue and substrate-cleavage experiments support negative regulation. Refine this broad TAS assertion to the negative child, while retaining the separate existing IEA and IGI assertions for that same specific term. Proposed replacements: negative regulation of chaperone-mediated autophagy |
| GO:1904715 negative regulation of chaperone-mediated autophagy | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The current rule supports the established contextual negative regulation of CMA. Reason: ARBA00088883 currently matches both the target FunFam and eukaryotic lineage conditions. The source-specific mechanism is CTSA-dependent LAMP2A proteolysis, supported independently by the original study. This is retained as a contextual regulatory output rather than generalized inhibition of all autophagy. |
| GO:1904715 negative regulation of chaperone-mediated autophagy | IGI PMID:12505983 Cathepsin A regulates chaperone-mediated autophagy through c... | KEEP AS NON CORE | Summary: CTSA negatively regulates CMA through LAMP2A turnover. Reason: The original study combines mouse knockout, human galactosialidosis-cell rescue and human PPCA cleavage of mouse LAMP2A. Reduced receptor degradation raises CMA, whereas restored CTSA protease activity lowers it. This supports a performed regulatory step. The original IGI and self WITH/FROM are retained; neither is replaced by a claim that both human splice products were tested. Supporting Evidence: PMID:12505983 PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a |
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Download this section (compressed HTML)Q: How do the 480- and 463-residue splice products differ in folding, processing, glycosidase protection and catalytic activity?
Q: What structural change in human NEU1 is induced by CTSA binding, and how does that activation differ from GLB1 stabilization?
Q: Which physiological substrates use CTSA carboxypeptidase activity, and how is this separated from the internal LAMP2A cleavage reported in CMA regulation?
Q: Can the target peptide entries for the NK-cell membrane and expressed-prostatic-secretion exosome screens be verified from their original supplemental datasets?
Q: The current fungal cpyA donor annotation links serine carboxypeptidase activity to an unrelated clinical publication. What is the correct source provenance for that individual annotation?
Q: Which GO term should represent peptide C-terminal deamidation, and when does this reaction versus amino-acid removal control tachykinin activity in vivo? Broad amidase activity needs semantic assessment for peptide carboxamides.
Experiment: Express and purify both precisely defined human splice products, confirm processing by mass spectrometry, and compare peptide hydrolysis, NEU1 activation and GLB1 protection under matched conditions.
Experiment: Reconstitute LAMP2A cleavage with separately purified CTSA precursor and mature forms, catalytic-site controls and mapped cleavage products to distinguish internal cleavage from C-terminal trimming.
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