SPINK5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0002787 negative regulation of antibacterial peptide production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara transfer from mouse Spink5 (Q148R4), whose annotation rests on increased epidermal antimicrobial activity in Spink5-deficient mice, attributed to unchecked kallikrein processing of cathelicidin. Reason: The mouse ortholog lies inside the same therian PAINT clade as human SPINK5 (PTN000099251), so the orthology transfer is sound. The regulatory link is mechanistic rather than a distant phenotype; LEKTI inhibits KLK5 and KLK7, and these proteases activate the cathelicidin precursor. It is a downstream consequence of the core kallikrein-inhibitor activity, so it is kept as non-core. Supporting Evidence: PMID:17012259 the serine proteases stratum corneum tryptic enzyme (SCTE, kallikrein 5) and stratum corneum chymotryptic protease (SCCE, kallikrein 7) were shown to control activation of the human cathelicidin precursor protein hCAP18 PMID:17012259 Epidermal extracts of these animals show a significant increase in antimicrobial activity compared with controls file:human/SPINK5/SPINK5-bioinformatics/RESULTS.md Its 12 leaves are the therian SPINK5 orthologs only
GO:0002809 negative regulation of antibacterial peptide biosynthetic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara transfer from mouse Spink5, from the same cathelicidin study as the antibacterial peptide production row. Reason: The mouse data concern proteolytic activation of the cathelicidin precursor by kallikreins, that is peptide maturation, not its biosynthesis. LEKTI affects which processed peptides accumulate, not synthesis of the precursor, so the production term (GO:0002787) captures the finding and the biosynthetic-process term overstates it. Supporting Evidence: PMID:17012259 The activity of cathelicidin is controlled by enzymatic processing of the proform (hCAP18 in humans) to a mature peptide
GO:0004867 serine-type endopeptidase inhibitor activity	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBD at the Theria speciation node PTN000099251, seeded by human SPINK5 itself. Reason: The node covers only the 12 therian SPINK5 orthologs in the PANTHER 19 PTHR10913 tree, and SPINK5 has direct biochemical evidence for the activity. Q9NQ38 appearing among the sources is expected, since its own experimental annotations seeded the IBD. The narrow node placement is a deliberate curator decision not to extend the activity to TMEFF2, the follistatins or invertebrate family members. Supporting Evidence: file:human/SPINK5/SPINK5-bioinformatics/RESULTS.md The PAINT node PTN000099251 (Theria, speciation) lies on the SPINK5 path. PMID:17596512 All LEKTI fragments, except D1, showed specific and differential inhibition of human kallikreins 5, 7, and 14.
GO:0004867 serine-type endopeptidase inhibitor activity	IDA PMID:10419450 LEKTI, a novel 15-domain type of human serine proteinase inh...	ACCEPT	Summary: Peptides of LEKTI purified from human blood filtrate; the HF7665 domain inhibited trypsin. Reason: Direct demonstration of inhibition of a serine endopeptidase by a native human LEKTI domain. Later work with recombinant full-length protein and furin-generated fragments confirms and extends the activity to KLK5, KLK7, KLK14, plasmin, cathepsin G and elastase. Supporting Evidence: PMID:10419450 An inhibitory effect of HF7665 on trypsin activity is demonstrated. PMID:12667078 rLEKTI inhibited the serine proteinases plasmin, subtilisin A, cathepsin G, human neutrophil elastase, and trypsin, but not chymotrypsin.
GO:0004867 serine-type endopeptidase inhibitor activity	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	ACCEPT	Summary: Recombinant LEKTI domains 1-6 expressed in HEK293T cells inhibited trypsin. Reason: Direct in vitro assay of a recombinant LEKTI fragment; consistent with the established core activity. Supporting Evidence: PMID:15680911 Recombinant LD-1-6 specifically inhibited the trypsin activity.
GO:0005576 extracellular region	IBA GO_REF:0000033	MODIFY	Summary: Family-root (Eukaryota) PAINT IBD for extracellular region, seeded by secreted follistatins and SPINK5. Reason: Correct, since LEKTI is a secreted protein and the family-root node is appropriate for a family of secreted Kazal/follistatin-domain proteins. For SPINK5 itself the evidence supports the more specific extracellular space (GO:0005615), where it is secreted between cells of the upper stratum granulosum and binds KLK5 in the stratum corneum. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000099217 · PTN000099217 SUPPORTS TRANSFER Eukaryota family-root node of PTHR10913 on the SPINK5 path; extracellular region is right for a secreted family, but target-specific evidence supports the child term extracellular space. Proposed replacements: extracellular space Supporting Evidence: PMID:15675955 is secreted in the extracellular spaces of the superficial stratum granulosum Reactome:R-HSA-8849646 In normal skin, this event occurs extracellularly in the stratum corneum of the skin.
GO:0005576 extracellular region	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	MODIFY	Summary: Pro-LEKTI and its processed fragments are secreted into the medium of transfected HEK293T cells. Reason: The secretion finding is sound; the in vivo evidence places the protein in the extracellular space between epidermal cells, so the more specific term is preferred. Proposed replacements: extracellular space Supporting Evidence: PMID:15680911 Pro-LEKTI is processed and secreted into the medium. PMID:15675955 is secreted in the extracellular spaces of the superficial stratum granulosum
GO:0005576 extracellular region	IEA GO_REF:0000044	MODIFY	Summary: UniProt subcellular location mapping (Secreted). Reason: Correct but general; extracellular space is supported by immunoelectron microscopy of human epidermis. Proposed replacements: extracellular space Supporting Evidence: PMID:15675955 is secreted in the extracellular spaces of the superficial stratum granulosum
GO:0005576 extracellular region	NAS PMID:10419450 LEKTI, a novel 15-domain type of human serine proteinase inh...	MODIFY	Summary: LEKTI peptides were isolated from human blood filtrate, and the precursor carries a signal peptide. Reason: Secretion is well established; the more specific extracellular space is preferred. Proposed replacements: extracellular space Supporting Evidence: PMID:10419450 We have succeeded in isolating two previously unknown polypeptides (HF6478 and HF7665) from human blood filtrate
GO:0005576 extracellular region	TAS Reactome:R-HSA-8849638	MODIFY	Summary: Reactome places dissociation of the SPINK5-KLK5 complex at low pH extracellularly in the upper layers of the skin. Reason: Correct; the reaction occurs in the intercellular space of the stratum corneum, so extracellular space is the more specific term. Proposed replacements: extracellular space Supporting Evidence: Reactome:R-HSA-8849638 In normal skin, this event occurs extracellularly in upper layers of the skin
GO:0005576 extracellular region	TAS Reactome:R-HSA-8849646	MODIFY	Summary: Reactome places binding of the SPINK5 D8-D9 fragment to KLK5 extracellularly in the stratum corneum. Reason: Correct; extracellular space is the more specific term for where the inhibitory complex forms. Proposed replacements: extracellular space Supporting Evidence: Reactome:R-HSA-8849646 In normal skin, this event occurs extracellularly in the stratum corneum of the skin.
GO:0005737 cytoplasm	IDA PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	MODIFY	Summary: Immunostaining of LEKTI in differentiated keratinocytes and epidermis. Reason: Intracellular LEKTI in keratinocytes is in the secretory pathway, in the ER and then in lamellar granules, before secretion. Cytoplasm is correct but general; the specific compartment shown by immunoelectron microscopy is the epidermal lamellar body, which the gene already carries by IDA. Proposed replacements: epidermal lamellar body Supporting Evidence: PMID:12915442 strongly expressed in the granular and uppermost spinous layers of the epidermis PMID:15675955 In normal skin, LEKTI, KLK7, and KLK5 were all found in the lamellar granule (LG) system, but were separately localized.
GO:0005783 endoplasmic reticulum	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	KEEP AS NON CORE	Summary: Pro-LEKTI colocalized with the ER in transfected HEK293T cells; signal-peptide deletion relocated it to the cytoplasm. Reason: ER localization reflects transit of a signal-peptide-bearing secretory protein, and is consistent with N-glycosylation and post-ER furin processing. It is real but not where the protein acts. Supporting Evidence: PMID:15680911 N-terminal signal peptide is required for LEKTI import into ER PMID:12915442 rapidly processed in a post-endoplasmic reticulum compartment
GO:0005789 endoplasmic reticulum membrane	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	MARK AS OVER ANNOTATED	Summary: Same HEK293T localization study as the ER row. Reason: LEKTI has a cleavable signal peptide (residues 1-22) and no transmembrane segment, and it is secreted, so within the ER it is expected to be lumenal. Immunofluorescence colocalization with ER markers does not resolve membrane from lumen. The ER row captures the finding; the membrane term overstates it. Supporting Evidence: PMID:15680911 Pro-LEKTI is processed and secreted into the medium.
GO:0005829 cytosol	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	MARK AS OVER ANNOTATED	Summary: The cited study reports cytoplasmic LEKTI only for a construct lacking the signal peptide. Reason: The abstract states that deleting the N-terminal signal peptide shifted LEKTI from the ER to the cytoplasm and destabilised it. That is the behaviour of an engineered mutant, not of the native protein, which enters the ER and is secreted. Without the full text this is not removed, but it does not describe where wild-type LEKTI resides. Supporting Evidence: PMID:15680911 Deletion of the N-terminal signal peptide of pro-LEKTI caused altered distribution of LEKTI from endoplasmic reticulum (ER) to cytoplasm and markedly reduced its stability
GO:0005938 cell cortex	IDA PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	KEEP AS NON CORE	Summary: Immunostaining of LEKTI in human epidermis and keratinocytes (abstract-only cache). Reason: Peripheral staining in granular-layer keratinocytes is consistent with lamellar granules near the apical plasma membrane before secretion. The full text was not available, so the curator's reading is not overruled, but the location is peripheral to function. Supporting Evidence: PMID:15675955 the LG system transports and secretes LEKTI earlier than KLK7 and KLK5
GO:0009913 epidermal cell differentiation	IDA PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	MARK AS OVER ANNOTATED	Summary: The study shows that LEKTI expression marks differentiated epidermal layers. Reason: Being a marker of differentiation is expression evidence, not participation. LEKTI acts extracellularly on kallikreins in the stratum granulosum and corneum. The keratinization and profilaggrin defects in Spink5-deficient mice are consequences of unchecked protease activity, a necessity relationship rather than LEKTI carrying out a step of keratinocyte differentiation. Supporting Evidence: PMID:12915442 LEKTI is a marker of epithelial differentiation PMID:15619623 This work identifies LEKTI as a key regulator of epidermal protease activity
GO:0016525 negative regulation of angiogenesis	TAS PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	REMOVE	Summary: Traceable author statement attributed to a study of LEKTI secretion and stability in HEK293T cells. Reason: The cited abstract concerns secretion, processing and trypsin inhibition and does not address angiogenesis. None of the LEKTI functional literature reviewed (kallikrein inhibition, Spink5-null mice, Netherton syndrome) reports a role in blood vessel formation, and a PubMed search for LEKTI or SPINK5 with angiogenesis returned no functional study. The claim is unsupported. Supporting Evidence: PMID:15680911 To assess the role of C-terminal domains and N-terminal signal peptide in LEKTI secretion
GO:0030154 cell differentiation	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: PAINT IBD at the Eumetazoa duplication node PTN000099219, seeded largely by follistatins and other family members. Reason: SPINK5 descends from PTN000099219, so the propagation is mechanically correct. The node spans follistatins, whose role in differentiation comes from activin binding, which SPINK5 lacks. SPINK5's own contribution, expression as a differentiation marker, is not participation. For SPINK5 the term is a broad developmental over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000099219 · PTN000099219 SUPPORTS SOURCE BUT NOT TARGET Eumetazoa duplication node above the follistatin and SPINK5 lineages; the follistatin seeds act in differentiation through activin binding, which SPINK5 lacks, and SPINK5's own evidence is expression as a differentiation marker rather than participation. Supporting Evidence: file:human/SPINK5/SPINK5-bioinformatics/RESULTS.md FST (human) \| PTN000099219 Eumetazoa \| duplication (distant paralog) PMID:12915442 LEKTI is a marker of epithelial differentiation
GO:0030198 extracellular matrix organization	TAS PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	MARK AS OVER ANNOTATED	Summary: Author statement that LEKTI inhibits serine proteinases involved in extracellular matrix remodelling. Reason: The statement describes the target proteases, not LEKTI. Inhibiting plasmin or trypsin in vitro does not show that LEKTI organises extracellular matrix. Its in vivo targets act on corneodesmosomes and stratum corneum proteins, not on ECM assembly. Supporting Evidence: PMID:15680911 LEKTI is a potent inhibitor of a family of serine proteinases involved in extracellular matrix remodeling
GO:0030414 peptidase inhibitor activity	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara transfer from mouse Spink5. Reason: Correct but general. The specific activity, serine-type endopeptidase inhibitor activity (GO:0004867), is supported by direct assays and already carried by the gene. Proposed replacements: serine-type endopeptidase inhibitor activity Supporting Evidence: PMID:17596512 All LEKTI fragments, except D1, showed specific and differential inhibition of human kallikreins 5, 7, and 14.
GO:0030855 epithelial cell differentiation	TAS PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	MARK AS OVER ANNOTATED	Summary: Statement from a study showing LEKTI is a marker of differentiated stratified epithelia. Reason: As for epidermal cell differentiation, expression in differentiated layers is not participation in differentiation. Supporting Evidence: PMID:12915442 LEKTI is a marker of epithelial differentiation
GO:0035315 hair cell differentiation	TAS PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	REMOVE	Summary: Probably derived from the hair shaft defect (trichorrhexis invaginata) of Netherton syndrome. Reason: In GO, hair cell differentiation covers the differentiation of mechanosensory hair cells such as those of the inner ear and lateral line. It does not cover hair follicle or hair shaft keratinocytes. Nothing links LEKTI to sensory hair cells. The Netherton hair shaft malformation is a downstream phenotype of unchecked protease activity, and would in any case map to hair follicle terms, not this one. Supporting Evidence: PMID:15619623 including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect
GO:0045580 regulation of T cell differentiation	TAS PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	MARK AS OVER ANNOTATED	Summary: Probably based on high thymic expression and the immune anomalies of Netherton syndrome. Reason: Thymic expression and atopy in Netherton syndrome do not show that LEKTI regulates T cell differentiation. The pro-Th2 inflammation in LEKTI deficiency arises from KLK5-PAR2-TSLP signalling in keratinocytes, independent of the adaptive immune system. Supporting Evidence: PMID:19414552 uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)-like lesions, independently of the environment and the adaptive immune system
GO:0048471 perinuclear region of cytoplasm	IDA PMID:15680911 Consequences of C-terminal domains and N-terminal signal pep...	KEEP AS NON CORE	Summary: Perinuclear staining of LEKTI in transfected HEK293T cells. Reason: Perinuclear signal is consistent with the ER and Golgi stages of the secretory pathway. It is a transit location, not a site of action. Supporting Evidence: PMID:15680911 N-terminal signal peptide is required for LEKTI import into ER
GO:0050777 negative regulation of immune response	TAS PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	KEEP AS NON CORE	Summary: Statement linking LEKTI deficiency to the immune and atopic features of Netherton syndrome. Reason: Mouse genetic and keratinocyte data show that LEKTI restrains a cell-autonomous inflammatory cascade in which free KLK5 activates PAR2 and NF-kappaB-driven TSLP expression. This is a regulatory consequence of kallikrein inhibition and is defensible as non-core. Supporting Evidence: PMID:19414552 unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor kappaB-mediated overexpression of TSLP
GO:0051884 regulation of timing of anagen	TAS PMID:12915442 LEKTI proteolytic processing in human primary keratinocytes,...	MARK AS OVER ANNOTATED	Summary: Probably derived from the hair abnormalities of Netherton syndrome. Reason: The Netherton hair defect is structural (fragile, invaginated hair shafts). No study reviewed shows that LEKTI controls when the hair cycle enters or leaves anagen. This is a downstream phenotype without evidence for the specific process. Supporting Evidence: PMID:15619623 hair malformation
GO:0097209 epidermal lamellar body	IDA PMID:15675955 LEKTI is localized in lamellar granules, separated from KLK5...	ACCEPT	Summary: Confocal and immunoelectron microscopy of human epidermis place LEKTI in lamellar granules, separate from KLK5 and KLK7. Reason: Direct ultrastructural localization in human skin. Lamellar granules are the vehicle that delivers LEKTI to the extracellular space ahead of its target kallikreins. Supporting Evidence: PMID:15675955 In normal skin, LEKTI, KLK7, and KLK5 were all found in the lamellar granule (LG) system, but were separately localized.

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