CTSF encodes cathepsin F, a papain-family cysteine endopeptidase that hydrolyzes proteins in acidic compartments. Its 484-residue precursor contains a signal peptide and an unusually long proregion with a cystatin-like segment; processing releases the 214-residue catalytic chain. Cathepsin F acts in lysosomes and can also be secreted by macrophages. It can cleave the MHC class II invariant chain and apolipoprotein B-containing lipoproteins in defined experimental settings. Biallelic CTSF defects cause adult-onset neuronal ceroid lipofuscinosis type B (CLN13).
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
CTSF_MATUREPRO_0000026203 (residues 271-484) | GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Reason: Cysteine endopeptidase activity is directly demonstrated for human cathepsin F. The actual current PTHR12411 tree places the exact 484-residue target below PTN000274640, where the corresponding IBD occurs; the historical donor set is reproduced and no target-path loss record was found. This supports the ancestral placement as well as the experimentally demonstrated target activity, without using donor number as an evidence score. |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Reason: EC 3.4.22.41 and direct human enzyme assays support this specific catalytic function. The current ARBA00028064 capture has no satisfied branch for the target among its 24 branches, so it does not independently reproduce the historical rule contribution. That rule-version limitation does not negate the separate EC premise or the observed cysteine endopeptidase activity; the original combined source object is preserved. |
| GO:0004197 cysteine-type endopeptidase activity | TAS PMID:9822672 Human cathepsin F. Molecular cloning, functional expression,... | ACCEPT | Reason: The original study expressed human cathepsin F in Pichia, measured blocked-peptide hydrolysis and E-64 sensitivity, and activated precursor at acidic pH or with pepsin. Its partial-clone sequence and proposed signal-independent trafficking were superseded by the full-length precursor sequence, but the positive enzyme measurements remain valid. The 302-residue sequence maps to precursor residues 183–484; the longer deposited partial clone maps to 147–484. |
| GO:0004197 cysteine-type endopeptidase activity | TAS Reactome:R-HSA-2130349 | ACCEPT | Reason: The actual Reactome reaction links catalyst activity 2130638 to cathepsin set 2130682, whose hasMember edge includes human CTSF entity 1181231 (Q9UBX1, residues 271–484). CTSF is represented as the performing protease. Recombinant human cathepsin F directly cleaves invariant-chain substrate in the supporting study. The broader cathepsin set is not evidence that every member has identical substrate specificity. |
| GO:0004197 cysteine-type endopeptidase activity | TAS Reactome:R-HSA-2130706 | ACCEPT | Reason: The actual Reactome reaction links catalyst activity 2130638 to cathepsin set 2130682, whose hasMember edge includes human CTSF entity 1181231 (Q9UBX1, residues 271–484). CTSF is represented as the performing protease. Recombinant human cathepsin F directly cleaves invariant-chain substrate in the supporting study. The broader cathepsin set is not evidence that every member has identical substrate specificity. |
| GO:0005515 protein binding | IPI PMID:15752368 Inhibitory properties of cystatin F and its localization in ... | KEEP AS NON CORE | Reason: O76096 is human cystatin F (CST7), distinct from cathepsin F. The original inhibition assays used human CTSF produced in Pichia and found tight inhibition by reduced monomeric cystatin F, including a CTSF Ki of 0.17 ± 0.05 nM with Z-Phe-Arg-AMC at pH 5.5. This supports the positive enzyme–inhibitor interaction. No evidence-backed, more informative binding class was established, so retain the supported generic assertion as non-core under the explicit retention policy in projects/CLINGEN_MENDELIAN.md, lines 2976–2978. CTSF is the inhibited protease, not the inhibitor. The current IntAct/MINT capture lacks this exact historical pair, which is not negative biological evidence. Supporting Evidence: |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | KEEP AS NON CORE | Reason: The extracellular IBD is on the actual target ancestry, and human monocyte-derived macrophage secretion of active CTSF is explicitly reported in the complete abstract of PMID:15184381. The original main Methods and Results for that paper remain unavailable here; no universal secretion rate or dominant extracellular role is inferred. The current IBD adds two zebrafish donors to the preserved historical source set, without changing the on-path placement. Retain this context-dependent location alongside the lysosomal core. Supporting Evidence: PMID:15184381 monocyte-derived macrophages were found to secrete active cathepsin F. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Reason: The official UniProt SL-0158 mapping denotes lysosome and agrees with the full precursor, acidic protease activity, mature-chain structural context and curated lysosomal-lumen pathway placement. It is not derived from cystatin F colocalization images, which describe a different protein. |
| GO:0005764 lysosome | TAS PMID:9822672 Human cathepsin F. Molecular cloning, functional expression,... | ACCEPT | Reason: Retain the biologically correct lysosomal annotation with explicit source limits. The original human partial construct in monkey COS-7 cells showed juxtanuclear vesicles resembling a separately imaged acidic-vesicle pattern; it did not establish direct dual-marker colocalization or distinguish lumen from the cytosolic membrane face. The complete human precursor subsequently resolved the missing signal sequence, and independent structural/Reactome evidence supports lysosomal cathepsin F. Acceptance therefore combines the original observation, curator judgment and independent evidence rather than treating the partial-construct image as a complete trafficking mechanism. |
| GO:0005773 vacuole | IBA GO_REF:0000033 | MODIFY | Reason: The broad vacuolar IBD is placed at PTN000274640 on the CTSF path, with the historical donor set retained. The qualifier is is_active_in. For the human target, Reactome events R-HSA-2130349 and R-HSA-2130706 explicitly include mature CTSF residues 271–484 in the lysosomal lumen, the volume enclosed by the lysosomal membrane. Refine the active compartment to GO:0043202 rather than stopping at the whole lysosome. This is a target-level scope refinement, not rejection of the valid ancestral placement or a lineage-specific loss claim. The engineered structure and partial-clone vesicle imaging do not independently establish precursor trafficking or the luminal membrane side. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000274640 The vacuole IBD is on the human target path and its historical donor set is preserved. Active mature human CTSF is explicitly modeled in the lysosomal lumen; this refines the broad compartment without asserting a loss or clade-placement error. Proposed replacements: lysosomal lumen Supporting Evidence: PMID:12225749 Cathepsin F is a lysosomal cysteine protease Reactome:R-HSA-2130349 Reactome:R-HSA-2130706 |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Reason: IPR000668 supplies a valid broad proteolysis mapping, and actual human cathepsin F catalyzes peptide-bond hydrolysis. This is performed proteolysis, not a process assigned only from disease or knockout necessity. |
| GO:0006508 proteolysis | TAS PMID:9822672 Human cathepsin F. Molecular cloning, functional expression,... | ACCEPT | Reason: The original recombinant human enzyme hydrolyzes blocked peptide substrates after activation, directly establishing proteolysis. The obsolete interpretation of its partial precursor does not invalidate the catalytic result. Supporting Evidence: |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:15752368 Inhibitory properties of cystatin F and its localization in ... | MODIFY | Reason: Refine the positive broad cysteine peptidase annotation to cysteine-type endopeptidase activity. The original Methods identify Pichia-expressed human CTSF, and its acidic Z-Phe-Arg-AMC activity is inhibited by cystatin F. Independent human CTSF enzyme and invariant-chain cleavage experiments establish the endopeptidase component more specifically. The cystatin F cellular-localization panels do not establish CTSF colocalization with LAMP2. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:15752368 Cystatin F tightly inhibited cathepsins F, K and V |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000002 | MODIFY | Reason: IPR000668 and IPR013128 correctly map the cysteine-peptidase family. The target is more specifically a cysteine endopeptidase: the human mature catalytic region produced as a GST fusion hydrolyzes the blocked substrate Z-Phe-Arg-AMC, and human enzyme also cleaves protein substrates in independent assays. This refines a sound broad domain assignment rather than diagnosing the InterPro source as invalid. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:10318784 cathepsin F produced in Escherichia coli as a fusion protein with glutathione S-transferase degrades the synthetic peptide benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin |
| GO:0019886 antigen processing and presentation of exogenous peptide antigen via MHC class II | TAS Reactome:R-HSA-2132295 | KEEP AS NON CORE | Reason: The actual pathway contains CTSF as a protease catalyst, and recombinant human cathepsin F directly converts mouse MHC-II-associated invariant-chain substrate toward CLIP in the original biochemical assay. Mouse macrophage experiments with cathepsin S/L deficiency and a nonselective cysteine-protease inhibitor support a contextual processing role, not a selective human CTSF knockout requirement or exclusive control of antigen presentation. Retain the performed proteolytic contribution as a non-core immune context. |
| GO:0030163 protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Reason: The protein-catabolism IBD lies on the CTSF ancestry, with the historical donor set preserved. Human recombinant cathepsin F directly degrades apoB-100 in LDL in vitro, supporting performed breakdown of a mature protein rather than a necessity-only inference. Protein catabolism is included alongside proteolysis in the catalytic core: the current ontology explicitly keeps proteolysis outside protein catabolism because peptide-bond cleavage also covers protein processing. The LDL experiment does not establish a universal substrate repertoire or an intact-cell turnover rate, and no disease or tissue pathway is inferred solely from expression. |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | KEEP AS NON CORE | Reason: The original Table S1 contains Q9UBX1/CTSF in the complete mass-spectrometry and matrisome sheets, classified as an ECM regulator with liver-associated sample detections. This supports the curated association with the extracted extracellular-matrix fraction. It does not make CTSF a structural matrix component or establish a universal extracellular location or a specific matrix-remodeling mechanism. Supporting Evidence: |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2130349 | ACCEPT | Reason: The reaction’s catalyst path explicitly includes mature human CTSF (entity 1181231, Q9UBX1 residues 271–484) in the lysosomal lumen. This is the enzyme’s curated working compartment, consistent with acidic catalysis and the mature protein; it is not inferred from the location of an inhibitor or substrate. |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-2130706 | ACCEPT | Reason: The reaction’s catalyst path explicitly includes mature human CTSF (entity 1181231, Q9UBX1 residues 271–484) in the lysosomal lumen. This is the enzyme’s curated working compartment, consistent with acidic catalysis and the mature protein; it is not inferred from the location of an inhibitor or substrate. |
| GO:0070062 extracellular exosome | HDA PMID:18570454 Proteomic analysis of exosomes from human neural stem cells ... | KEEP AS NON CORE | Reason: The full original Table 2 on page 3478 identifies cathepsin F precursor (gi6467382) with two matched peptides in fraction 3 from human HB1.F3 neural-stem-cell supernatant. The study combines flow field-flow fractionation, TEM and LC–MS/MS. Retain the fraction-associated exosome annotation as contextual; it does not demonstrate CTSF-dependent vesicle biogenesis or localization of all cellular CTSF to exosomes. Supporting Evidence: |
| GO:1903561 extracellular vesicle | HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi... | KEEP AS NON CORE | Reason: The original public PXD000608 MaxQuant tables identify Q9UBX1/CTSF in the human cerebrospinal-fluid extracellular-vesicle samples. The protein-group entry reports seven unique peptides, and five independently located peptide-table rows literally list Q9UBX1 with signal in EV samples. The group’s internal peptide-ID list does not align with those five rows in the distributed files, so all seven are not claimed independently verified. Main-paper Methods remain unavailable here; retain the positive fraction association with those limits, without assigning vesicle production or an exclusive vesicular pool. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which endogenous human protein substrates account for CTSF-dependent neuronal lysosomal function, and how does their cleavage connect to CLN13 pathology?
Q: What controls activation and compartmental delivery of the full 484-residue precursor, and does its cystatin-like proregion have a separable inhibitory activity or primarily an intramolecular regulatory role?
Q: Which CTSF molecular form is present in extracellular vesicles: the intact proenzyme, the processed mature chain, or both, and is the vesicle-associated enzyme catalytically active?
Experiment: Compare full-length human CTSF, an active-site mutant and a processing-defective precursor in human neuronal cells, mapping lysosomal substrate cleavage and rescue with matched protein abundance and localization.
Experiment: Map N termini and catalytic activity of endogenous lysosomal and secreted CTSF, using compartment-purity controls to distinguish processed active enzyme from precursor or fraction carryover.
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