cpi-2

Gene 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 Review

GO Term	Evidence	Action	Reason
GO:0004869 cysteine-type endopeptidase inhibitor activity	IEA GO_REF:0000120	ACCEPT	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.
GO:0005737 cytoplasm	IEA GO_REF:0000118	REMOVE	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.
GO:0031982 vesicle	IEA GO_REF:0000118	KEEP AS NON CORE	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.
GO:0004869 cysteine-type endopeptidase inhibitor activity	IDA PMID:15664654 Bm-CPI-2, a cystatin from Brugia malayi nematode parasites, ...	ACCEPT	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.
GO:0019828 aspartic-type endopeptidase inhibitor activity	IDA PMID:15664654 Bm-CPI-2, a cystatin from Brugia malayi nematode parasites, ...	MODIFY	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. Proposed replacements: cysteine-type endopeptidase inhibitor activity
GO:0004869 cysteine-type endopeptidase inhibitor activity	IDA PMID:11301256 Bm-CPI-2, a cystatin homolog secreted by the filarial parasi...	ACCEPT	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.

Core Functions

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:

cysteine-type endopeptidase inhibitor activity

Supporting Evidence:

PMID:11301256
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.
PMID:15664654
one face of the protein blocking papain-like proteases, and the other able to inhibit legumains such as asparaginyl endopeptidase (AEP).

Gene Description

Existing Annotations Review

Core Functions

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.

References

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