cpi-2

id: A0A0K0IP23
gene_symbol: cpi-2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:6279
  label: Brugia malayi
description: >-
  CPI-2 (Bm-CPI-2) is a secreted cystatin-family (MEROPS I25) cysteine protease
  inhibitor from the human filarial parasite Brugia malayi. The protein is
  synthesized as a precursor with an N-terminal signal peptide and is released
  into the extracellular environment. Like vertebrate type 2 cystatins, it is
  bifunctional: one face of the cystatin fold blocks papain-like (clan CA, family
  C1) cysteine proteases such as cathepsins L, S and B, while a distinct second
  site, dependent on an asparagine residue (Asn-77), inhibits the legumain-type
  asparaginyl endopeptidase (AEP/LGMN, clan CD, family C13), which is itself a
  cysteine peptidase. Through inhibition of these endosomal/lysosomal proteases,
  CPI-2 interferes with the MHC class II antigen-processing pathway of antigen
  presenting cells, blocking both antigenic peptide generation and invariant
  chain (CD74/Ii) degradation. CPI-2 is expressed across all life-cycle stages
  of the parasite and is thought to act at the host-parasite interface as an
  immunomodulator that helps the long-lived parasite evade or dampen host
  adaptive immune responses.
existing_annotations:
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (InterPro/PANTHER/ARBA) of cysteine-type
      endopeptidase inhibitor activity. This is the defining, well-supported
      molecular function of a cystatin and is directly corroborated by
      experimental IDA annotations for this gene (PMID:11301256,
      PMID:15664654). Accept as core.
    action: ACCEPT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000118
  qualifier: located_in
  review:
    summary: >-
      TreeGrafter phylogenetic propagation to cytoplasm. CPI-2 is a secreted
      protein with an N-terminal signal peptide (residues 1-25) and acts
      extracellularly and within host endosomal/lysosomal compartments; its
      established biology is extracellular, not cytoplasmic. This is a generic,
      poorly supported localization propagated across the broad cystatin
      PANTHER family and is not informative for the secreted function of this
      protein.
    action: REMOVE
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000118
  qualifier: located_in
  review:
    summary: >-
      TreeGrafter phylogenetic propagation to vesicle. This generic
      compartment term is consistent with a secreted protein trafficking
      through the secretory pathway and with action in host
      endosomes/lysosomes, but it is uninformative and not directly supported
      by any data for CPI-2 itself. Retain only as a non-core, low-information
      localization.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:15664654
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence. Murray et al. (2005) showed by
      site-directed mutagenesis and inhibition assays that recombinant Bm-CPI-2
      blocks papain-like proteases (cathepsins) and inhibits the cysteine
      peptidase asparaginyl endopeptidase (AEP/legumain). Both targets are
      cysteine-type endopeptidases, so this term is correct and represents the
      core molecular function. Accept as core.
    action: ACCEPT
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:15664654
  qualifier: enables
  review:
    summary: >-
      This annotation appears to mis-type the inhibited enzyme. The
      experimental target in Murray et al. (2005) is asparaginyl endopeptidase
      (AEP/legumain), which is a cysteine peptidase (MEROPS clan CD, family
      C13), not an aspartic-type endopeptidase. Cystatins inhibit papain-like
      (C1) and legumain-type (C13) cysteine proteases; there is no evidence
      that Bm-CPI-2 inhibits any aspartic-type (e.g. pepsin/cathepsin D)
      protease. The underlying experimental finding (AEP inhibition) is sound
      but is correctly captured by the cysteine-type endopeptidase inhibitor
      term; the aspartic-type label is biologically incorrect for legumain.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0004869
      label: cysteine-type endopeptidase inhibitor activity
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:11301256
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence. Manoury et al. (2001) showed that
      recombinant Bm-CPI-2 inhibits multiple lysosomal cysteine protease
      activities of human B-lymphocyte endosomes/lysosomes, blocks in vitro
      processing of tetanus toxin antigen, and reduces MHC class II-restricted
      antigen presentation. This directly supports cysteine-type endopeptidase
      inhibitor activity as the core molecular function. Accept as core.
    action: ACCEPT
core_functions:
- description: >-
    Inhibition of papain-like (C1) and legumain-type (C13) cysteine
    endopeptidases, including host cathepsins L/S/B and asparaginyl
    endopeptidase (AEP/legumain), thereby modulating host endosomal/lysosomal
    proteolysis and MHC class II antigen processing.
  molecular_function:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  supported_by:
  - reference_id: PMID:11301256
    supporting_text: >-
      CPI-2 blocked the hydrolysis of synthetic substrates favored by two
      different families of lysosomal cysteine proteases and blocked the in
      vitro processing of the tetanus toxin antigen by purified lysosome
      fractions.
  - reference_id: PMID:15664654
    supporting_text: >-
      one face of the protein blocking papain-like proteases, and the other
      able to inhibit legumains such as asparaginyl endopeptidase (AEP).
references:
- id: GO_REF:0000118
  title: TreeGrafter-generated GO annotations
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Source of generic, phylogenetically propagated cytoplasm and vesicle
      localizations that are not specifically supported for this secreted
      protein.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Electronic family-based assignment of cysteine-type endopeptidase
      inhibitor activity, consistent with the experimental annotations.
- id: PMID:11301256
  title: Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi,
    inhibits class II MHC-restricted antigen processing.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary functional study; demonstrates inhibition of lysosomal cysteine
      proteases and interference with MHC class II antigen processing by
      recombinant Bm-CPI-2. Abstract verified against cached publication.
- id: PMID:15664654
  title: Bm-CPI-2, a cystatin from Brugia malayi nematode parasites, differs from
    Caenorhabditis elegans cystatins in a specific site mediating inhibition of the
    antigen-processing enzyme AEP.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Primary study mapping the bifunctional inhibitory activity; Asn-77
      mutagenesis ablates AEP (legumain, a cysteine peptidase) inhibition while
      papain-like protease inhibition is largely retained. Confirms cysteine-type
      (not aspartic-type) endopeptidase inhibition. Abstract verified against
      cached publication.