CASP14

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: CASP14 is well-documented to localize to the cytoplasm in keratinocytes, particularly in the granular layer and stratum corneum where it performs its core function [PMID:11175259 "Subcellular localization shows cytoplasm"; UniProt P31944]. This annotation is supported by experimental evidence and represents the primary site of CASP14 activity in cleaving filaggrin. Supporting Evidence: file:human/CASP14/CASP14-deep-research-falcon.md model: Edison Scientific Literature
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Cytosol is a more specific subcompartment of cytoplasm. CASP14 localization to cytosol is supported by HPA data (GO_REF:0000052) and Reactome pathways showing it acts in the cytosolic compartment [Reactome:R-HSA-6814387, Reactome:R-HSA-8934819]. This is consistent with its role in cleaving cytoplasmic filaggrin.
GO:0043525 positive regulation of neuron apoptotic process	IBA GO_REF:0000033	REMOVE	Summary: This annotation is incorrect. CASP14 is a non-apoptotic caspase specifically involved in keratinocyte terminal differentiation and cornification, not neuronal apoptosis [PMID:10203698 "does not elicit cell death"; deep-research "Non-apoptotic caspase involved in epidermal differentiation"]. CASP14 is not expressed in neurons and does not participate in apoptotic pathways. This is likely a phylogenetic inference error based on caspase family membership.
GO:0004197 cysteine-type endopeptidase activity	IEA GO_REF:0000002	ACCEPT	Summary: CASP14 is indeed a cysteine-type endopeptidase (EC 3.4.22.-) with a catalytic cysteine-histidine dyad [UniProt P31944; PMID:10203698 "cysteine-aspartic acid protease"]. This annotation accurately represents the core catalytic activity and is supported by TAS evidence (PMID:10203698).
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: CASP14 has been detected in the nucleus of keratinocytes [PMID:11175259 "Nucleus localization"; PMID:23377137 "nuclear localization in keratinocytes"], though this is not its primary site of action. The nuclear localization may be relevant to its role in facilitating DNA degradation during cornification via ICAD cleavage. However, since the core function is cytoplasmic filaggrin cleavage, this should be kept as non-core.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasm localization is correct and supported by UniProt subcellular location mapping, consistent with the IBA annotation already accepted.
GO:0006508 proteolysis	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Proteolysis is too general. While CASP14 does perform proteolysis, this term does not capture the specific biological context. The protein cleaves filaggrin during cornification - a more specific term like "keratinization" or "cornification" better represents its function.
GO:0008233 peptidase activity	IEA GO_REF:0000120	REMOVE	Summary: This is redundant with the more specific "cysteine-type endopeptidase activity" already annotated. Peptidase activity is an overly general parent term that adds no additional information.
GO:0008234 cysteine-type peptidase activity	IEA GO_REF:0000120	REMOVE	Summary: This is essentially redundant with "cysteine-type endopeptidase activity" (GO:0004197) already accepted. The distinction between peptidase and endopeptidase is minor and both capture the same core activity.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	REMOVE	Summary: Hydrolase activity is an extremely general parent term. All proteases are hydrolases, but this provides no useful functional information beyond what is captured by the more specific cysteine-type endopeptidase activity.
GO:0030154 cell differentiation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Cell differentiation is too broad. CASP14 functions specifically in keratinocyte terminal differentiation, not general cell differentiation. The more specific terms "keratinization" and "epidermis development" better capture its role.
GO:0001533 cornified envelope	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CASP14 is present in cornified cells and plays a role in cornification [UniProt P31944; deep-research "Formation of the cornified envelope"]. However, this is a cellular component term describing a structure, not the primary location where CASP14 performs its enzymatic activity. CASP14 acts before and during cornified envelope formation in the cytosol/cytoplasm.
GO:0045095 keratin filament	IEA GO_REF:0000107	REMOVE	Summary: While filaggrin (a CASP14 substrate) aggregates keratin filaments, there is no direct evidence that CASP14 itself localizes to keratin filaments. This appears to be an over-inference from the functional association. CASP14 cleaves filaggrin in the cytosol, not specifically at keratin filaments.
GO:0005515 protein binding	IPI PMID:24872419 Mesotrypsin and caspase-14 participate in prosaposin process...	REMOVE	Summary: Protein binding is uninformative per curation guidelines. PMID:24872419 discusses CASP14 and prosaposin processing, but the specific molecular function is better captured by "cysteine-type endopeptidase activity" - CASP14 cleaves protein substrates as a protease, not merely binds them. Supporting Evidence: PMID:24872419 2014 May 28. Mesotrypsin and caspase-14 participate in prosaposin processing: potential relevance to epidermal permeability barrier formation.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Protein binding is uninformative per curation guidelines. PMID:25416956 is a large-scale interactome study. Generic protein binding does not describe CASP14's actual molecular function, which is proteolytic cleavage of specific substrates. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Nucleoplasm localization is supported by immunofluorescence data from HPA. This is consistent with CASP14's role in facilitating DNA degradation via ICAD cleavage during cornification. However, this is secondary to its primary cytoplasmic function.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosol localization is well-supported by experimental evidence from HPA immunofluorescence, consistent with the IBA annotation already accepted.
GO:0005829 cytosol	TAS Reactome:R-HSA-6814387	ACCEPT	Summary: Cytosol localization confirmed by Reactome pathway "CASP14 cleaves filaggrin", consistent with other evidence.
GO:0005829 cytosol	TAS Reactome:R-HSA-8934819	ACCEPT	Summary: Cytosol localization confirmed by Reactome pathway "Cytoplasmic proteases cleave Profilaggrin producing Filaggrin".
GO:0031424 keratinization	TAS PMID:18309324 No death without life: vital functions of apoptotic effector...	ACCEPT	Summary: Keratinization is a core function of CASP14. The protein is essential for proper keratinocyte terminal differentiation [PMID:18309324 "vital functions of apoptotic effectors"; UniProt P31944 "involved in keratinocyte differentiation"]. CASP14 cleaves filaggrin during this process, generating natural moisturizing factors critical for the keratinization program. Supporting Evidence: PMID:18309324 Feb 29. No death without life: vital functions of apoptotic effectors.
GO:0070268 cornification	TAS PMID:18309324 No death without life: vital functions of apoptotic effector...	ACCEPT	Summary: Cornification is THE core function of CASP14 [PMID:18309324; UniProt P31944 "required for cornification"; deep-research "orchestrating cornification"]. CASP14 is the predominant caspase in the stratum corneum and is essential for processing filaggrin into NMFs and facilitating nuclear degradation during cornification. This is the most accurate representation of CASP14 function. Supporting Evidence: PMID:18309324 Feb 29. No death without life: vital functions of apoptotic effectors.
GO:0005634 nucleus	IDA PMID:23377137 Expression of caspase-14 and keratin-19 in the human epiderm...	KEEP AS NON CORE	Summary: Nucleus localization confirmed by IDA evidence from developmental study [PMID:23377137 "nuclear localization in keratinocytes"], consistent with other evidence. This is secondary to cytoplasmic function. Supporting Evidence: PMID:23377137 Epub 2013 Feb 3. Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development.
GO:0005737 cytoplasm	IDA PMID:23377137 Expression of caspase-14 and keratin-19 in the human epiderm...	ACCEPT	Summary: Cytoplasm localization confirmed by IDA evidence from developmental study [PMID:23377137], consistent with other evidence. Supporting Evidence: PMID:23377137 Epub 2013 Feb 3. Expression of caspase-14 and keratin-19 in the human epidermis and appendages during fetal skin development.
GO:0004197 cysteine-type endopeptidase activity	TAS PMID:10203698 Identification of a new caspase homologue: caspase-14.	ACCEPT	Summary: Cysteine-type endopeptidase activity confirmed by TAS evidence from the original CASP14 identification paper [PMID:10203698], consistent with IEA annotation. Supporting Evidence: PMID:10203698 Identification of a new caspase homologue: caspase-14.
GO:0008544 epidermis development	TAS PMID:10203698 Identification of a new caspase homologue: caspase-14.	ACCEPT	Summary: Epidermis development is supported by CASP14's role in barrier formation during development [PMID:10203698 "role in ontogenesis and skin physiology"; deep-research "essential developmental program"]. This accurately captures CASP14's function in epidermal maturation, though cornification/keratinization are more specific. Supporting Evidence: PMID:10203698 Identification of a new caspase homologue: caspase-14.

Gene Description

Existing Annotations Review

Core Functions

CASP14 acts as a cysteine-type endopeptidase to cleave filaggrin during cornification, generating natural moisturizing factors essential for skin barrier function

References

Deep Research

Falcon

Perplexity

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