id: P08236
gene_symbol: GUSB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GUSB encodes beta-glucuronidase (EC 3.2.1.31), a lysosomal exoglycosidase of glycoside
  hydrolase family 2 (GH2). It catalyses the hydrolysis of terminal, non-reducing
  beta-D-glucuronic acid residues from glycosaminoglycans, acting in the stepwise exolytic
  lysosomal degradation of heparan sulfate, dermatan sulfate, chondroitin sulfate and
  hyaluronan (reaction: a beta-D-glucuronoside + H2O = D-glucuronate + an alcohol). The
  active enzyme is a homotetramer that localises to the lysosomal lumen and is a
  mannose-6-phosphate-tagged, receptor-trafficked lysosomal hydrolase; it is also detectable
  extracellularly (secretion, neutrophil granule exocytosis) and in exosomes. Inherited
  deficiency of beta-glucuronidase causes mucopolysaccharidosis type VII (Sly syndrome), an
  autosomal recessive lysosomal storage disorder with tissue accumulation of undegraded
  glycosaminoglycans and a clinical spectrum ranging from lethal hydrops fetalis to milder
  adult-onset forms.
alternative_products:
- name: 1 (Long)
  id: P08236-1
- name: 2 (Short)
  id: P08236-2
  sequence_note: VSP_001799
- name: '3'
  id: P08236-3
  sequence_note: VSP_054830
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to extracellular region. Beta-glucuronidase is
      primarily a lysosomal hydrolase, but it is secreted and detected in the
      extracellular space/exosomes, so the location is not wrong; it is peripheral to the
      core lysosomal catabolic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      GUSB is fundamentally a lysosomal enzyme; extracellular presence reflects secretion,
      granule exocytosis and exosomal release rather than its principal site of action.
      Retained as non-core.
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of beta-glucuronidase activity (EC 3.2.1.31), the
      defining molecular function of GUSB. Supported across evidence types and by the
      catalytic reaction annotated in UniProt.
    action: ACCEPT
    reason: >-
      This is the core molecular function. GUSB hydrolyses terminal non-reducing
      beta-D-glucuronic acid residues; the reaction is directly documented, and enzymatic
      activity was measured on human enzyme.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "Reaction=a beta-D-glucuronoside + H2O = D-glucuronate + an alcohol;"
    - reference_id: PMID:3468507
      supporting_text: >-
        the cDNA sequence for human placental beta-glucuronidase
        (beta-D-glucuronoside glucuronosohydrolase, EC 3.2.1.31)
- term:
    id: GO:0030214
    label: hyaluronan catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for hyaluronan catabolism. Purified human
      beta-glucuronidase is active on hyaluronic acid oligosaccharides, consistent with an
      exolytic role in stepwise hyaluronan degradation.
    action: KEEP_AS_NON_CORE
    reason: >-
      GUSB contributes to hyaluronan turnover as one of the terminal exoglycosidases, but
      hyaluronan degradation is one of several GAG substrates; kept as a specific
      non-core catabolic process under the general glycosaminoglycan catabolic role.
    supported_by:
    - reference_id: PMID:7354065
      supporting_text: >-
        Both forms of these enzymes are active on 4-methyl
        umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
        chondroitin, and hyaluronic acid
- term:
    id: GO:0030200
    label: heparan sulfate proteoglycan catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for heparan sulfate catabolism. GUSB removes terminal
      beta-D-glucuronic acid residues during the stepwise lysosomal degradation of heparan
      sulfate; deficiency causes glycosaminoglycan storage (MPS VII).
    action: ACCEPT
    reason: >-
      Consistent with the enzyme's exolytic role in glycosaminoglycan degradation and with
      the lysosomal storage of undegraded GAGs on deficiency. A verified core catabolic
      process.
    supported_by:
    - reference_id: PMID:1465145
      supporting_text: >-
        results from lysosomal storage of undegraded glycosaminoglycans in the spleen,
        liver, kidney, cornea, brain and skeletal system
- term:
    id: GO:0030207
    label: chondroitin sulfate proteoglycan catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation for chondroitin sulfate catabolism. Purified human
      beta-glucuronidase is active on chondroitin and chondroitin-6-sulfate
      oligosaccharides, supporting its role in exolytic chondroitin/dermatan sulfate
      degradation.
    action: ACCEPT
    reason: >-
      Directly supported by measured enzymatic activity on chondroitin-6-SO4 and
      chondroitin oligosaccharides and by UniProt's degradation-of-dermatan-sulfate
      function. A verified core catabolic process.
    supported_by:
    - reference_id: PMID:7354065
      supporting_text: >-
        Both forms of these enzymes are active on 4-methyl
        umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
        chondroitin, and hyaluronic acid
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "FUNCTION: Plays an important role in the degradation of dermatan and"
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation for signaling receptor binding. This is a bare
      protein-binding-type term that does not describe an informative molecular function
      of a lysosomal hydrolase; the underlying interaction is recognition of the enzyme's
      mannose-6-phosphate tag by the mannose-6-phosphate receptor, a trafficking event.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Signaling receptor binding" over-interprets the mannose-6-phosphate-receptor
      recognition that traffics GUSB to the lysosome; it does not represent a signaling
      function of GUSB. Marked as over-annotation per curation guidance to avoid
      uninformative binding terms.
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) annotation for carbohydrate binding. Substrate (glycosaminoglycan)
      binding is intrinsic to the catalytic activity and is captured more informatively by
      the beta-glucuronidase activity term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Carbohydrate binding here reflects substrate engagement by the active site and is
      subsumed by GO:0004566 beta-glucuronidase activity; as a standalone binding term it
      is an over-annotation.
- term:
    id: GO:0004553
    label: hydrolase activity, hydrolyzing O-glycosyl compounds
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) mapping to the parent O-glycosyl hydrolase term based on GH2 domain
      signatures. Correct but less specific than the beta-glucuronidase activity term.
    action: ACCEPT
    reason: >-
      A correct, more general parent of GO:0004566. Acceptable as a broader IEA mapping; the
      specific activity is captured separately.
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA, ARBA/EC/RHEA) assignment of beta-glucuronidase activity from EC
      3.2.1.31 and RHEA:17633. Consistent with the core molecular function.
    action: ACCEPT
    reason: >-
      Correct EC/RHEA-based electronic mapping of the defining catalytic activity.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "Reaction=a beta-D-glucuronoside + H2O = D-glucuronate + an alcohol;"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt SubCell (IEA) mapping to lysosome, matching the annotated lysosomal
      subcellular location. This is the core site of action.
    action: ACCEPT
    reason: >-
      GUSB is a lysosomal hydrolase; localisation to the lysosome is well established and
      central to its catabolic function.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO (IEA) mapping to the broad carbohydrate metabolic process term. Correct
      but general; the specific glycosaminoglycan catabolic processes are more informative.
    action: ACCEPT
    reason: >-
      A correct high-level parent process. Acceptable as broader IEA context.
- term:
    id: GO:0030214
    label: hyaluronan catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA (IEA) annotation for hyaluronan catabolism, duplicating the IBA/IDA assignments.
      Supported by measured activity on hyaluronic acid oligosaccharides.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but one of several GAG substrate processes; kept as a specific non-core
      catabolic process.
    supported_by:
    - reference_id: PMID:7354065
      supporting_text: >-
        Both forms of these enzymes are active on 4-methyl
        umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
        chondroitin, and hyaluronic acid
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2318373
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) assertion of beta-glucuronidase activity in the context of
      hyaluronan/GAG degradation reactions. Consistent with the core molecular function.
    action: ACCEPT
    reason: >-
      Reactome-curated pathway assertion of the defining catalytic activity.
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036068
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) assertion of beta-glucuronidase activity (GlcA-beta1,3-GlcNAc
      hydrolysis reaction). Consistent with the core molecular function.
    action: ACCEPT
    reason: >-
      Reactome-curated assertion of the defining catalytic activity in CS/HS degradation.
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036070
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) assertion of beta-glucuronidase activity (CS/HS precursor hydrolysis).
      Consistent with the core molecular function.
    action: ACCEPT
    reason: >-
      Reactome-curated assertion of the defining catalytic activity.
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: IDA
  original_reference_id: PMID:7354065
  qualifier: enables
  review:
    summary: >-
      Direct assay (IDA) of beta-glucuronidase activity: highly purified human placental
      beta-glucuronidase hydrolyses 4-methylumbelliferyl-beta-D-glucuronide and GAG-derived
      oligosaccharides. This is direct experimental support for the core molecular function.
    action: ACCEPT
    reason: >-
      Experimental demonstration of catalytic activity of the human enzyme on both a
      synthetic beta-D-glucuronide substrate and physiological GAG oligosaccharides.
    supported_by:
    - reference_id: PMID:7354065
      supporting_text: >-
        Both forms of these enzymes are active on 4-methyl
        umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
        chondroitin, and hyaluronic acid
- term:
    id: GO:0030214
    label: hyaluronan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:7354065
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Direct assay (IDA) supporting a role in hyaluronan catabolism: purified human
      beta-glucuronidase acts on hyaluronic acid oligosaccharides, consistent with exolytic
      participation in hyaluronan degradation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by measured activity on hyaluronic acid hexasaccharides; retained as a
      specific non-core catabolic process (one of several GAG substrates).
    supported_by:
    - reference_id: PMID:7354065
      supporting_text: >-
        Both forms of these enzymes are active on 4-methyl
        umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
        chondroitin, and hyaluronic acid
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation of extracellular localisation via neutrophil azurophil
      granule exocytosis (degranulation). Real but peripheral to the core lysosomal role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects secretion/degranulation of the lysosomal enzyme; peripheral to the core
      lysosomal catabolic function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) annotation of extracellular localisation via ficolin-1-rich granule
      exocytosis. Peripheral to the core lysosomal role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects granule exocytosis of the enzyme; peripheral to core function.
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the azurophil granule lumen of neutrophils, consistent
      with GUSB being stored in these lysosome-related granules and released on
      degranulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Azurophil granules are lysosome-related organelles; localisation is plausible but
      cell-type-specific and peripheral to the core lysosomal catabolic role.
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the ficolin-1-rich granule lumen of neutrophils.
      Cell-type-specific storage location, peripheral to the core lysosomal role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Neutrophil granule localisation; peripheral to the core catabolic function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:25645918
  qualifier: located_in
  review:
    summary: >-
      IDA localisation to the extracellular region, from a study of proteins secreted from
      neutrophil azurophilic granules into pathogen-infected sputum. Consistent with
      secretion of the enzyme; peripheral to the core lysosomal role.
    action: KEEP_AS_NON_CORE
    reason: >-
      Extracellular detection reflects granule secretion; peripheral to core function.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:20028034
  qualifier: enables
  review:
    summary: >-
      IPI annotation (with UniProtKB:P08169, the cation-independent mannose-6-phosphate
      receptor). In this study human beta-glucuronidase was used as a mannose-6-phosphate
      ligand purified on a CI-MPR affinity column; the interaction is receptor recognition
      of the enzyme's M6P tag for lysosomal trafficking, not a signaling function. This is
      a bare, uninformative binding term for GUSB.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The M6P-receptor interaction is a trafficking/recognition event, not signaling
      receptor engagement by GUSB; annotating GUSB with "signaling receptor binding"
      over-interprets it. Retained as over-annotation rather than removed (experimental
      IPI). Per curation guidance, bare binding terms are uninformative.
    supported_by:
    - reference_id: PMID:20028034
      supporting_text: >-
        a carbohydrate moiety, mannose 6-phosphate (Man-6-P) found on N-linked glycans of
        lysosomal enzymes
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:20028034
  qualifier: enables
  review:
    summary: >-
      IPI annotation (with UniProtKB:P08169) for protein domain specific binding. Same
      underlying CI-MPR/M6P recognition as above; a bare, uninformative binding term for a
      lysosomal hydrolase.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Captures the mannose-6-phosphate-receptor recognition of GUSB; uninformative as a
      standalone binding function. Retained as over-annotation rather than removed
      (experimental IPI).
    supported_by:
    - reference_id: PMID:20028034
      supporting_text: >-
        a carbohydrate moiety, mannose 6-phosphate (Man-6-P) found on N-linked glycans of
        lysosomal enzymes
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HDA) detection of GUSB in urinary/prostatic exosomes.
      Consistent with the secreted/exosomal presence of the enzyme; peripheral to core
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosomal detection is a peripheral localisation typical of many lysosomal/secreted
      proteins; not the core site of action.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HDA) detection of GUSB in an NK-cell membrane-proteome
      fraction. GUSB is a soluble lumenal enzyme; membrane co-fractionation is likely
      association with membrane-bounded compartments rather than an integral membrane role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GUSB has no transmembrane domain and is a soluble lysosomal/secreted enzyme; the
      generic "membrane" term from a membrane-fraction proteomics screen over-interprets a
      co-purification. Retained as over-annotation.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HDA) detection of GUSB in urinary exosomes, duplicating
      the exosome localisation. Peripheral to core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Exosomal detection; peripheral localisation, not the core site of action.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2318373
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen, the core compartment where GUSB
      acts as a soluble exoglycosidase in GAG degradation.
    action: ACCEPT
    reason: >-
      Lysosomal lumen is the core site of action for this soluble lysosomal hydrolase.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036068
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen (CS/HS degradation context). Core
      compartment of action.
    action: ACCEPT
    reason: >-
      Core lysosomal lumen localisation.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9036070
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen (CS/HS degradation context). Core
      compartment of action.
    action: ACCEPT
    reason: >-
      Core lysosomal lumen localisation.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1678854
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen (GUSB tetramer hydrolyses CS/HS
      precursor). Core compartment of action.
    action: ACCEPT
    reason: >-
      Core lysosomal lumen localisation.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162226
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen (GUSB tetramer hydrolyzes
      GlcA-beta1,3-GlcNAc). Core compartment of action.
    action: ACCEPT
    reason: >-
      Core lysosomal lumen localisation.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2162227
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localisation to the lysosomal lumen (GUSB tetramer hydrolyses (HA)2).
      Core compartment of action.
    action: ACCEPT
    reason: >-
      Core lysosomal lumen localisation.
    supported_by:
    - reference_id: file:human/GUSB/GUSB-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome."
- term:
    id: GO:0004566
    label: beta-glucuronidase activity
  evidence_type: TAS
  original_reference_id: PMID:3468507
  qualifier: enables
  review:
    summary: >-
      TAS annotation of beta-glucuronidase activity from the cDNA cloning/expression paper,
      which expressed catalytically active human beta-glucuronidase (EC 3.2.1.31) in COS
      cells. Supports the core molecular function.
    action: ACCEPT
    reason: >-
      Author-stated activity of the human enzyme; the same paper reports functional
      expression of active beta-glucuronidase.
    supported_by:
    - reference_id: PMID:3468507
      supporting_text: >-
        the cDNA sequence for human placental beta-glucuronidase
        (beta-D-glucuronoside glucuronosohydrolase, EC 3.2.1.31)
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: TAS
  original_reference_id: PMID:3468507
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to the broad carbohydrate metabolic process term from the cloning
      paper. Correct but general; more specific GAG catabolic processes better capture the
      role.
    action: ACCEPT
    reason: >-
      Correct high-level process; acceptable as broader context.
- term:
    id: GO:0006027
    label: glycosaminoglycan catabolic process
  evidence_type: TAS
  original_reference_id: PMID:1465145
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation to glycosaminoglycan catabolic process. Beta-glucuronidase deficiency
      causes lysosomal accumulation of undegraded glycosaminoglycans (Sly syndrome / MPS
      VII), directly establishing its role in GAG catabolism.
    action: ACCEPT
    reason: >-
      This is the core biological process. Loss of GUSB blocks stepwise GAG degradation and
      leads to lysosomal GAG storage, as shown genetically in the MPS VII model.
    supported_by:
    - reference_id: PMID:1465145
      supporting_text: >-
        An inherited deficiency of beta-glucuronidase in humans, mice and dogs causes
        mucopolysaccharidosis VII (Sly syndrome), a progressive degenerative disease
    - reference_id: PMID:1465145
      supporting_text: >-
        results from lysosomal storage of undegraded glycosaminoglycans in the spleen,
        liver, kidney, cornea, brain and skeletal system
core_functions:
- description: >-
    Lysosomal beta-glucuronidase (EC 3.2.1.31): hydrolyses terminal, non-reducing
    beta-D-glucuronic acid residues from glycosaminoglycans, functioning as an exolytic
    exoglycosidase in the stepwise lysosomal degradation of heparan sulfate, dermatan
    sulfate, chondroitin sulfate and hyaluronan.
  molecular_function:
    id: GO:0004566
    label: beta-glucuronidase activity
  directly_involved_in:
  - id: GO:0006027
    label: glycosaminoglycan catabolic process
  locations:
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: PMID:7354065
    supporting_text: >-
      Both forms of these enzymes are active on 4-methyl
      umbelliferyl-beta-D-glucuronide and on the hexasaccharides of chondroitin-6-SO4,
      chondroitin, and hyaluronic acid
  - reference_id: PMID:1465145
    supporting_text: >-
      results from lysosomal storage of undegraded glycosaminoglycans in the spleen,
      liver, kidney, cornea, brain and skeletal system
  - reference_id: file:human/GUSB/GUSB-uniprot.txt
    supporting_text: "Reaction=a beta-D-glucuronoside + H2O = D-glucuronate + an alcohol;"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1465145
  title: Reversal of pathology in murine mucopolysaccharidosis type VII by somatic
    cell gene transfer.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes that beta-glucuronidase deficiency causes MPS VII (Sly
      syndrome) with lysosomal storage of undegraded glycosaminoglycans, supporting the
      glycosaminoglycan catabolic process annotation.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale proteomics; supports peripheral exosomal localisation (HDA) only.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Membrane-fraction proteomics; supports only a peripheral/co-fractionation membrane
      detection, not an integral-membrane function of the soluble enzyme.
- id: PMID:20028034
  title: Residues essential for plasminogen binding by the cation-independent mannose
    6-phosphate receptor.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Full text verified. The paper is about the CI-MPR's plasminogen-binding site; human
      beta-glucuronidase is used only as a mannose-6-phosphate reference ligand purified on
      a CI-MPR affinity column. It supports M6P-receptor recognition (a trafficking event),
      not "signaling receptor binding" or a signaling function of GUSB; used here as basis
      for the over-annotation calls on the IPI binding terms.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Exosome proteomics; supports peripheral exosomal localisation (HDA) only.
- id: PMID:25645918
  title: Human neutrophils secrete bioactive paucimannosidic proteins from azurophilic
    granules into pathogen-infected sputum.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Neutrophil secretion study; supports peripheral extracellular localisation of the
      secreted enzyme.
- id: PMID:3468507
  title: Cloning, sequencing, and expression of cDNA for human beta-glucuronidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Provides the human beta-glucuronidase cDNA/sequence, confirms EC
      3.2.1.31, and demonstrates functional expression of the active enzyme.
- id: PMID:7354065
  title: Multiple kinetic forms of beta-glucuronidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Direct enzymatic assays of highly purified human placental
      beta-glucuronidase on a synthetic beta-D-glucuronide and on chondroitin/hyaluronan
      oligosaccharides; the IDA basis for the catalytic activity and GAG/hyaluronan
      catabolism annotations.
- id: Reactome:R-HSA-1678854
  title: GUSB tetramer hydrolyses CS/HS precursor
  findings: []
- id: Reactome:R-HSA-2162226
  title: GUSB tetramer hydrolyzes GlcA-β1,3-GlcNAc
  findings: []
- id: Reactome:R-HSA-2162227
  title: GUSB tetramer hydrolyses (HA)2
  findings: []
- id: Reactome:R-HSA-2318373
  title: Defective GUSB does not hydrolyse (HA)2
  findings: []
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9036068
  title: Defective GUSB does not hydrolyse GlcA-β1,3-GlcNAc
  findings: []
- id: Reactome:R-HSA-9036070
  title: Defective GUSB does not hydrolyse CS/HS precursor
  findings: []