Affinage

SPINK5

Serine protease inhibitor Kazal-type 5 · UniProt Q9NQ38

Length
1064 aa
Mass
120.7 kDa
Annotated
2026-04-28
100 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPINK5 encodes LEKTI, a multi-domain serine protease inhibitor that is the master regulator of kallikrein-mediated desquamation in stratified epithelia. LEKTI is synthesized as a high-molecular-weight precursor in differentiated keratinocytes, rapidly cleaved by furin into multiple bioactive single- and multi-domain fragments that are stored in lamellar granules separately from their targets KLK5, KLK7, and KLK14, and secreted into the extracellular space of the stratum granulosum where they potently inhibit these kallikreins through tight-binding, pH-dependent interactions — with acidic pH triggering kallikrein release to permit corneodesmosomal proteolysis at the skin surface (PMID:17596512, PMID:16307483, PMID:15675955). Loss-of-function mutations in SPINK5 cause Netherton syndrome, characterized by uncontrolled serine protease activity leading to premature corneodesmosome degradation, lipid processing enzyme proteolysis, lamellar membrane disorganization, and severe skin barrier failure (PMID:11874482, PMID:16601670). The common E420K variant alters furin cleavage priorities, preventing formation of the most potent KLK5-inhibitory fragment (D6–D9) and resulting in enhanced protease activity, reduced desmoglein-1, and increased TSLP expression (PMID:22730493). Mesotrypsin (PRSS3) functions upstream of LEKTI by both activating pro-KLK5/KLK7 and degrading LEKTI inhibitory domains, placing LEKTI within a multi-tiered proteolytic cascade controlling epidermal homeostasis (PMID:24390132).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Establishing that SPINK5 loss of function leads to excess serine protease activity in the stratum corneum linked the gene product to direct protease inhibition during desquamation and confirmed its role in Netherton syndrome pathogenesis.

    Evidence Enzymatic activity assays of trypsin-like activity in stratum corneum of NS patients with characterized SPINK5 mutations versus controls

    PMID:11874482

    Open questions at the time
    • Single lab, no identification of specific protease targets
    • Mechanism of inhibition not determined
  2. 2003 High

    Defining furin as the processing protease and mapping LEKTI precursor cleavage into discrete C-terminal fragments established the biosynthetic pathway from full-length precursor to secreted inhibitory peptides.

    Evidence Furin inhibitor treatment of keratinocytes blocked processing; in vitro cleavage of recombinant 145 kDa precursor by purified furin reconstituted the fragments

    PMID:12915442

    Open questions at the time
    • Exact number and identity of all physiological fragments not yet known
    • N-terminal fragments not characterized
  3. 2003 High

    Demonstrating that full-length recombinant LEKTI inhibits multiple serine proteinases (plasmin, subtilisin A, cathepsin G, elastase, trypsin) via a noncompetitive mechanism requiring disulfide bonds established the biochemical class of inhibition.

    Evidence Kinetic inhibition assays with baculovirus-expressed LEKTI against a panel of serine and cysteine proteinases, with DTT inactivation

    PMID:12667078

    Open questions at the time
    • Physiological kallikrein targets (KLK5, KLK7) not yet tested
    • Domain-specific contributions not resolved
  4. 2005 High

    Showing that LEKTI and its kallikrein targets are co-stored in lamellar granules but in separate compartments, with LEKTI secreted ahead of KLK5/KLK7, explained how premature protease activation is prevented and why LEKTI absence causes suprabasal splitting.

    Evidence Immunoelectron microscopy and confocal microscopy of normal and NS epidermis

    PMID:15675955

    Open questions at the time
    • Molecular basis of differential secretion timing unknown
    • Mechanism of compartment segregation within lamellar granules not defined
  5. 2005 High

    Domain-resolved kinetics revealed that LEKTI fragments containing domains 6–12 are potent, pH-sensitive inhibitors of KLK5 (Ki ~1–6 nM at pH 8, weaker at pH 5), establishing pH as the control switch for kallikrein release during desquamation.

    Evidence Recombinant LEKTI domain fragments tested against purified KLK5 and KLK7 with equilibrium and kinetic measurements at pH 8.0 and 5.0

    PMID:16307483 PMID:16307658

    Open questions at the time
    • In vivo pH gradient across stratum corneum not directly correlated with fragment dissociation
    • Contribution of each individual domain not fully deconvolved
  6. 2006 High

    Correlating the magnitude of KLK5/KLK7 hyperactivity with barrier defect severity in NS patients, and showing downstream proteolysis of lipid-processing enzymes and corneodesmosomes, mapped the full pathogenic cascade from LEKTI loss to barrier failure.

    Evidence Protease activity assays, electron microscopy of lamellar membranes, DSG1/DSC1 western blotting in NS patient epidermis stratified by clinical severity

    PMID:16601670

    Open questions at the time
    • Relative contributions of KLK5 vs. KLK7 vs. other proteases to each downstream effect not separated
    • Compensatory DSG3/DSC3 upregulation mechanism not defined
  7. 2007 High

    Comprehensive mapping of furin-generated LEKTI fragments and their differential KLK5/KLK7/KLK14 inhibitory profiles — identifying D8–D11 as the strongest KLK5 inhibitor forming an irreversible tight-binding complex released at acidic pH — provided the definitive biochemical framework for LEKTI-mediated protease regulation.

    Evidence Panel of LEKTI antibodies, kinetic analysis of all major fragments against KLK5, KLK7, KLK14 at multiple pH values

    PMID:17596512 PMID:17989726

    Open questions at the time
    • Crystal structure of LEKTI–KLK complex not available
    • Contribution of in vivo co-factors or lipid environment not tested
  8. 2010 Medium

    Lentiviral SPINK5 rescue of NS keratinocytes restored normal epidermal architecture in organotypic and xenograft models, with bystander correction of surrounding cells, confirming that secreted LEKTI is both necessary and sufficient for barrier function.

    Evidence Lentiviral transduction of NS keratinocytes, organotypic culture, mouse xenograft engraftment

    PMID:20877344

    Open questions at the time
    • Long-term durability of correction not assessed
    • Single lab study without independent replication
  9. 2011 High

    Mapping the complete proteolytic activation cascade of LEKTI in vivo, including three new processing intermediates, and showing that fragment-to-KLK5 ratios in the uppermost epidermis are compatible with fine-tuned inhibitory control refined the quantitative model of desquamation regulation.

    Evidence Antibody mapping, N-terminal sequencing, site-specific mutagenesis, quantitative fragment analysis in human epidermis

    PMID:21697885

    Open questions at the time
    • Dynamic turnover rates of individual fragments in vivo unknown
    • Redundancy with other protease inhibitors not assessed
  10. 2012 High

    The common E420K polymorphism was shown to redirect furin cleavage within the D6–D7 linker, preventing formation of the D6–D9 fragment with peak KLK5-inhibitory activity, thereby linking a common SPINK5 variant to enhanced protease activity, DSG1 loss, and TSLP-driven inflammation.

    Evidence In vitro furin cleavage assays of wild-type vs. E420K LEKTI, in situ zymography, DSG1 and TSLP immunohistochemistry in 420KK patient epidermis

    PMID:22730493

    Open questions at the time
    • Population-level impact on atopic dermatitis risk not mechanistically resolved in this study
    • Whether other processing enzymes compensate for altered furin cleavage unknown
  11. 2014 High

    Identifying mesotrypsin (PRSS3) as a protease that activates pro-KLK5/KLK7 and simultaneously degrades LEKTI inhibitory domains — while being resistant to LEKTI inhibition — positioned mesotrypsin as an upstream regulator of the LEKTI–KLK axis in desquamation.

    Evidence In vitro activation and degradation assays with recombinant mesotrypsin, proximity ligation assay in human skin sections

    PMID:24390132

    Open questions at the time
    • In vivo genetic evidence for mesotrypsin's role (e.g. PRSS3 knockout) not available
    • Regulation of mesotrypsin activity itself not defined
  12. 2016 Medium

    Demonstrating compensatory LEKTI upregulation in atopic dermatitis lesions, correlating with retained corneodesmosomes and compact hyperkeratosis despite elevated KLK7 protein, revealed that LEKTI acts as a bidirectional rheostat — its deficiency causes over-desquamation while its excess causes under-desquamation.

    Evidence Western blot, immunostaining, electron microscopy, in situ zymography on AD patient tape-stripped corneocytes

    PMID:27769847

    Open questions at the time
    • Mechanism driving LEKTI upregulation in AD not identified
    • Whether LEKTI excess is cause or consequence of compact hyperkeratosis not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis of pH-dependent LEKTI–KLK complex dissociation (no crystal structure available); the in vivo hierarchy and redundancy among LEKTI fragments and other epidermal protease inhibitors; genetic validation of mesotrypsin's in vivo role upstream of LEKTI–KLK; and whether LEKTI's reported effects on Wnt/β-catenin and STAT3 signaling in cancer represent direct mechanisms or indirect consequences of protease regulation.
  • No structural model of any LEKTI domain–KLK complex
  • In vivo genetic epistasis between PRSS3 and SPINK5 not tested
  • SPINK5-STAT3 interaction mechanism not established beyond indirect Co-IP

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1500931 Cell-Cell communication 3 R-HSA-168256 Immune System 3
Partners
DSG1FURINKLK14KLK5KLK7PRSS3

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 LEKTI is produced as a precursor rapidly cleaved by furin, generating multiple single or multidomain fragments (D1, D5, D6, D8-D11, D9-D15) that are secreted in keratinocytes and epidermis. All LEKTI fragments except D1 specifically and differentially inhibit human kallikreins 5, 7, and 14, with the strongest inhibition by D8-D11 toward KLK5 in a rapid, irreversible, tight-binding complex. pH governs this interaction, with acidic pH releasing active KLK5 from the complex, enabling precisely regulated KLK5 activity and corneodesmosomal cleavage in the superficial stratum corneum. Biochemical analysis with panel of LEKTI antibodies, kinetic analysis of inhibitory activity on serine proteases, pH-dependent interaction assays Molecular biology of the cell High 17596512
2003 LEKTI is expressed as a 145 kDa full-length protein and a 125 kDa isoform in differentiated keratinocytes; both are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into C-terminal fragments of 42, 65, and 68 kDa by furin. Treatment with a furin inhibitor blocked processing, and in vitro cleavage of recombinant 145 kDa precursor by furin generated the 65 and 68 kDa C-terminal fragments directly. Monoclonal/polyclonal antibody detection, furin inhibitor treatment of keratinocytes, in vitro cleavage assay with recombinant furin, conditioned media analysis Human molecular genetics High 12915442
2002 Loss-of-function SPINK5 mutations cause markedly elevated trypsin-like hydrolytic activity in stratum corneum of Netherton syndrome patients, supporting the model that SPINK5-derived LEKTI peptides normally inhibit serine proteases to regulate corneocyte desquamation. SPINK5 mutation characterization, enzymatic activity assay of trypsin-like hydrolytic activity in stratum corneum from NS patients vs. controls The Journal of investigative dermatology Medium 11874482
2005 LEKTI and its kallikrein targets KLK5 and KLK7 are all localized within lamellar granules of normal epidermis but are separately stored; LEKTI is secreted earlier than KLK7 and KLK5, preventing premature loss of stratum corneum integrity. In Netherton syndrome skin lacking LEKTI, an abnormal split in the superficial stratum granulosum is observed. Confocal laser scanning microscopy and immunoelectron microscopy of human epidermis; comparison with NS patient skin The Journal of investigative dermatology High 15675955
2005 LEKTI domain 6 is a potent inhibitor of hK5 (KLK5) and hK7 (KLK7) at nanomolar concentrations, while LEKTI domain 15 inhibits plasmin. This identifies KLK5 and KLK7 as specific physiological targets of LEKTI domain 6 relevant to skin desquamation and inflammation. In vitro inhibitory activity assays of recombinant LEKTI domains 6 and 15 against purified kallikreins hK5 and hK7 The British journal of dermatology High 16307658
2005 LEKTI fragments containing Kazal domains 6-8 and 9-12 potently inhibit recombinant KLK5 (Ki 1.2–5.5 nM at pH 8.0; 10–20 nM at pH 5.0) with slow dissociation rates (t1/2 ~20–25 min), indicating tight and specific binding. Only fragment 6-9' was a good inhibitor of KLK7 (Ki 11 nM at pH 8.0), with rapidly reversible kinetics. Lower pH reduces inhibitory potency, consistent with a pH-controlled release mechanism. Recombinant protein expression, kinetic and equilibrium binding studies measuring Ki, kass, and kdis at pH 8.0 and 5.0 Biological chemistry High 16307483
2003 Full-length recombinant LEKTI (rLEKTI) inhibits serine proteinases plasmin, subtilisin A, cathepsin G, human neutrophil elastase, and trypsin via a noncompetitive mechanism (Ki values: 27 nM for plasmin to 849 nM for trypsin), but does not inhibit chymotrypsin or cysteine proteinases. Disulfide bonds are required for inhibitory activity. Baculovirus/insect cell recombinant expression, kinetic inhibition assays, DTT inactivation experiments Biochemistry High 12667078
2006 The magnitude of serine protease (KLK5, KLK7) activation in the stratum corneum correlates with permeability barrier defect severity and clinical severity in Netherton syndrome, and inversely with residual LEKTI expression. LEKTI co-localizes with KLK5 and KLK7 in the stratum corneum and inhibits both. Excess serine protease activity in NS leads to proteolysis of lipid hydrolases (beta-glucocerebrosidase, acidic sphingomyelinase), disorganization of lamellar membranes, and degradation of corneodesmosomes via DSG1/DSC1 cleavage, with compensatory upregulation of DSG3/DSC3. Patient phenotype correlation with SP activity assays, LEKTI immunolocalization, lamellar membrane analysis by electron microscopy, desmoglein/desmocollin western blotting The Journal of investigative dermatology High 16601670
2007 LEKTI domain specificity for inhibiting SC protease activities was mapped: domains 6-12 predominantly inhibit trypsin-like (Phe-Ser-Arg-) activity; domains 12-15 inhibit plasmin- and trypsin-like (Pro-Phe-Arg-) activities; all domains inhibit chymotrypsin-like activity; no domains inhibit furin-like activity. KLK levels are significantly elevated in the SC and serum of NS patients, and LEKTI domain length correlates with protease inhibitory activity and clinical severity. Recombinant LEKTI domain proteins, protease inhibition assays with SC extracts, KLK quantification by immunoassay in NS patients The Journal of investigative dermatology High 17989726
2011 A proteolytic activation cascade of LEKTI in the epidermis was defined by antibody mapping, N-terminal sequencing, and site-specific mutagenesis, identifying most physiologically generated LEKTI polypeptides and three new processing intermediates. The most effective LEKTI fragments against desquamation-related KLKs were shown to inhibit KLK-mediated proteolysis of desmoglein-1, and fragment ratios relative to active KLK5 in the uppermost epidermis are compatible with fine-tuned inhibitory control. Antibody mapping, N-terminal sequencing, site-specific mutagenesis, KLK proteolysis assays, fragment quantification in epidermis The Journal of investigative dermatology High 21697885
2012 The common LEKTI E420K variant (Glu420Lys) increases furin-dependent cleavage within the D6-D7 linker region, reversing cleavage priorities during LEKTI activation and preventing formation of the D6-D9 fragment with the strongest KLK5-inhibitory activity. This results in enhanced KLK5, KLK7, and elastase-2 activities in 420KK epidermis, reduced DSG1 expression, accelerated profilaggrin proteolysis, and increased TSLP expression. In vitro furin cleavage assays, in situ and gel zymographies, immunohistochemistry, western blot in patient-derived 420KK epidermis Human molecular genetics High 22730493
2006 SPINK5 generates three classes of transcripts by alternative pre-mRNA processing, encoding three LEKTI isoforms differing in their C-terminal portion (15-domain, 13-domain, and a longer isoform with a 30-amino-acid insertion between domains 13 and 14). All isoforms are translated in differentiated keratinocytes and generate distinct secreted C-terminal proteolytic fragments from a similar cleavage site. RT-PCR, protein expression analysis in differentiated keratinocytes, N-terminal sequencing of secreted fragments The Journal of investigative dermatology Medium 16374478
2010 Lentiviral SPINK5 gene delivery to NS keratinocytes restored LEKTI expression in previously deficient cells. Genetically corrected NS keratinocytes formed normal epidermal architecture in organotypic culture and in vivo mouse/human skin grafts, including a bystander benefit in surrounding uncorrected cells, consistent with LEKTI being a secreted protein. Lentiviral transduction of NS keratinocytes, organotypic culture, in vivo xenograft engraftment model, immunofluorescence for LEKTI and epidermal markers Molecular therapy Medium 20877344
2014 Keratinocyte-specific mesotrypsin (PRSS3) activates pro-KLK5 and pro-KLK7 in vitro, and degrades LEKTI inhibitory domains (D2, D2-5, D2-6, D2-7, D5, D6, D6-9, D7, D7-9, D10-15) that normally suppress KLK activity—whereas mesotrypsin itself is not inhibited by these LEKTI fragments. Proximity ligation assay demonstrated close association between mesotrypsin and KLKs in granular to cornified layers, placing mesotrypsin upstream of KLK activation and LEKTI degradation in desquamation. In vitro activation assays of KLK zymogens by mesotrypsin, LEKTI domain inhibition/degradation assays, immunoelectron microscopy, proximity ligation assay in human skin sections The Journal of investigative dermatology High 24390132
2006 LEKTI and KLK5, KLK6, and KLK14 are expressed in the pituitary gland. SPINK5 inhibitory domain fragments suppress KLK4, KLK5, and KLK14 activities in vitro. KLKs 4-6, 8, 13, and 14 cleave human growth hormone (hGH) in vitro, generating isoforms, suggesting SPINK5/LEKTI regulates KLK-mediated hGH processing in the pituitary. RT-PCR and immunohistochemistry for expression in pituitary, in vitro recombinant hGH digestion by KLKs, N-terminal sequencing of fragments, LEKTI fragment inhibition of KLK activities Clinica chimica acta Medium 17140555
2019 SPINK5 overexpression in esophageal cancer cells inhibits the Wnt/β-catenin signaling pathway by inhibiting GSK3β phosphorylation and promoting β-catenin protein degradation (shown in combination with LiCl or MG-132 treatment). SPINK5 overexpression in vivo significantly inhibits esophageal cancer cell growth. Co-immunoprecipitation confirmed an indirect interaction between SPINK5 (LEKTI) and STAT3. Western blot for Wnt/β-catenin components, LiCl/MG-132 chemical epistasis, in vivo tumor growth assay, Co-IP for SPINK5-STAT3 interaction Cancer medicine Low 30868765
2022 miR-5100 targets SPINK5 mRNA (confirmed by luciferase reporter assay), reducing LEKTI expression and thereby activating STAT3 phosphorylation, promoting melanoma cell metastasis via epithelial-mesenchymal transition. Metformin inhibits the miR-5100/SPINK5/STAT3 pathway. Co-IP confirmed an indirect interaction between SPINK5 and STAT3. Luciferase reporter assay for miR-5100 targeting SPINK5, migration/wound healing assays, Co-IP, in vivo metastasis model in mice Cellular & molecular biology letters Medium 35705923
2019 Compound K (CK), an active ginsenoside metabolite, increases SPINK5 gene promoter activity and SPINK5/LEKTI expression in UVB-irradiated keratinocytes, resulting in decreased downstream KLK5, KLK7, and PAR2 expression, and restored epidermal barrier function (transepidermal water loss, hydration) in UVB-irradiated and DNCB-induced atopic dermatitis mouse models. Transactivation (promoter) assay, RT-PCR, western blot in HaCaT cells, TEWL and hydration measurement, histology in mouse models Journal of ginseng research Medium 33192123
2016 In atopic dermatitis lesions, KLK7 secretion from lamellar granules is impaired and LEKTI expression is increased, correlating with retention of corneodesmosomes and compact hyperkeratosis. In situ zymography showed that KLK activity on tape-stripped corneocytes from AD lesions was not significantly elevated despite increased KLK7 protein levels, implicating upregulated LEKTI as a compensatory mechanism suppressing desquamation. Western blot, immunostaining, electron microscopy, in situ zymography on AD patient tape-stripped corneocytes The Journal of investigative dermatology Medium 27769847

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Progress in neuro-psychopharmacology & biological psychiatry 836 20471444
2013 Thrombosis: tangled up in NETs. Blood 673 24366358
2019 DAMPs and NETs in Sepsis. Frontiers in immunology 492 31736963
2021 A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clinical reviews in allergy & immunology 475 32740860
2020 The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Frontiers in immunology 428 33042107
1998 Perineuronal nets: past and present. Trends in neurosciences 414 9881847
2021 Perineuronal nets stabilize the grid cell network. Nature communications 295 33431847
2009 Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral research 255 19945487
2007 LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Molecular biology of the cell 237 17596512
2020 Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses. Cells 219 32276504
2021 Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis. Cancers 192 34503307
2016 The Emerging Role of NETs in Venous Thrombosis and Immunothrombosis. Frontiers in immunology 191 27446071
2015 At the Bench: Neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases. Journal of leukocyte biology 178 26432901
2020 Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression. Advances in biological regulation 166 32773102
2018 Insecticide-treated nets for preventing malaria. The Cochrane database of systematic reviews 166 30398672
2008 New insights into transcriptional regulation by H-NS. Current opinion in microbiology 166 18387844
2013 Neutrophil extracellular traps (NETs) - formation and implications. Acta biochimica Polonica 165 23819131
1993 The NS 3 nonstructural protein of flaviviruses contains an RNA triphosphatase activity. Virology 163 8212562
2003 LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Human molecular genetics 162 12915442
2002 Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. The Journal of investigative dermatology 154 11874482
2022 Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality. International immunopharmacology 153 35032828
2015 Simplified Human Neutrophil Extracellular Traps (NETs) Isolation and Handling. Journal of visualized experiments : JoVE 150 25938591
2002 Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. The Journal of investigative dermatology 144 11841556
2019 Untangling "NETosis" from NETs. European journal of immunology 135 30629284
2003 Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. The British journal of dermatology 135 12752122
2006 Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. The Journal of investigative dermatology 134 16601670
2019 Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis. Critical care (London, England) 120 30961634
2019 DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth. Oncoimmunology 117 31428515
2005 LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. The Journal of investigative dermatology 116 15675955
1994 The chromatin-associated protein H-NS. Biochimie 106 7748941
2016 Social amoebae trap and kill bacteria by casting DNA nets. Nature communications 104 26927887
2023 Molecular Mechanisms of Neutrophil Extracellular Trap (NETs) Degradation. International journal of molecular sciences 102 36902325
2000 Oligomerization of the chromatin-structuring protein H-NS. Molecular microbiology 102 10844682
1990 NS-1 and NS-2 proteins may act synergistically in the cytopathogenicity of parvovirus MVMp. Virology 96 2137660
2003 Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Genes and immunity 95 14551605
2005 hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. The British journal of dermatology 94 16307658
2018 Platelets, NETs and cancer. Thrombosis research 89 29703474
2016 Structure and function of bacterial H-NS protein. Biochemical Society transactions 87 27913665
1976 Morphogenesis of lines and nets. Differentiation; research in biological diversity 86 1010155
2014 Silencing by H-NS potentiated the evolution of Salmonella. PLoS pathogens 79 25375226
2005 Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Biological chemistry 76 16307483
2003 Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 76 12667078
2012 The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Human molecular genetics 75 22730493
2021 Significance of NETs Formation in COVID-19. Cells 74 33466589
2021 Neutrophil Extracellular Traps (NETs) in Severe SARS-CoV-2 Lung Disease. International journal of molecular sciences 74 34445556
2019 Perineuronal Nets and Their Role in Synaptic Homeostasis. International journal of molecular sciences 72 31443560
2007 Correlation between SPINK5 gene mutations and clinical manifestations in Netherton syndrome patients. The Journal of investigative dermatology 71 17989726
2017 Understanding the Entanglement: Neutrophil Extracellular Traps (NETs) in Cystic Fibrosis. Frontiers in cellular and infection microbiology 70 28428948
2021 Neutrophil Extracellular Traps (NETs) in Cancer Metastasis. Cancers 67 34885240
2022 The potential roles of type I interferon activated neutrophils and neutrophil extracellular traps (NETs) in the pathogenesis of primary Sjögren's syndrome. Arthritis research & therapy 64 35854322
2011 Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. The Journal of investigative dermatology 60 21697885
2016 NETs in cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 59 27614687
2015 H-NS and RNA polymerase: a love-hate relationship? Current opinion in microbiology 59 25638302
2021 A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins. Viruses 56 33670641
2008 Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk. The Journal of allergy and clinical immunology 55 18774391
2010 Ex-vivo gene therapy restores LEKTI activity and corrects the architecture of Netherton syndrome-derived skin grafts. Molecular therapy : the journal of the American Society of Gene Therapy 53 20877344
2019 H-NS uses an autoinhibitory conformational switch for environment-controlled gene silencing. Nucleic acids research 52 30597093
2009 Diverse functions of perineuronal nets. Acta neurobiologiae experimentalis 52 20048772
2023 Neutrophil extracellular traps (NETs) in cardiovascular diseases: From molecular mechanisms to therapeutic interventions. Kardiologia polska 51 38189504
2020 NETs in APS: Current Knowledge and Future Perspectives. Current rheumatology reports 51 32845378
2012 Neutrophil extracellular traps (NETs) and infection-related vascular dysfunction. Blood reviews 50 23021640
2010 Imaging of NETs with PET radiopharmaceuticals. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... 49 20168283
2020 Detection, Visualization, and Quantification of Neutrophil Extracellular Traps (NETs) and NET Markers. Methods in molecular biology (Clifton, N.J.) 48 31729003
2024 Astrocytes require perineuronal nets to maintain synaptic homeostasis in mice. Nature neuroscience 47 39020018
2019 Aggregated NETs Sequester and Detoxify Extracellular Histones. Frontiers in immunology 44 31572386
2014 Keratinocyte-specific mesotrypsin contributes to the desquamation process via kallikrein activation and LEKTI degradation. The Journal of investigative dermatology 44 24390132
2022 Association between neutrophil extracellular traps (NETs) and thrombosis in antiphospholipid syndrome. Thrombosis research 43 35561448
2011 Association of SPINK5 gene polymorphisms with atopic dermatitis in Northeast China. Journal of the European Academy of Dermatology and Venereology : JEADV 43 21585560
2022 Radiomics in pulmonary neuroendocrine tumours (NETs). La Radiologia medica 42 35538389
2021 Staphylococcus aureus induces neutrophil extracellular traps (NETs) and neutralizes their bactericidal potential. Computational and structural biotechnology journal 42 34194670
2019 A novel tumor suppressor SPINK5 targets Wnt/β-catenin signaling pathway in esophageal cancer. Cancer medicine 40 30868765
2016 Caught in the Net: Perineuronal Nets and Addiction. Neural plasticity 40 26904301
2004 Three-periodic nets and tilings: minimal nets. Acta crystallographica. Section A, Foundations of crystallography 39 15507732
2021 Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Comprehensive Physiology 38 33577121
1996 H-NS regulates OmpF expression through micF antisense RNA in Escherichia coli. Journal of bacteriology 38 8655567
2016 Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis. The Journal of investigative dermatology 36 27769847
2022 Aging hampers neutrophil extracellular traps (NETs) efficacy. Aging clinical and experimental research 34 35920993
2021 Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs). Therapeutic advances in medical oncology 34 34484432
2014 Exploring the interaction of N/S compounds with a dicopper center: tyrosinase inhibition and model studies. Inorganic chemistry 34 25415587
2005 Polymorphisms in SPINK5 are not associated with asthma in a Dutch population. The Journal of allergy and clinical immunology 34 15753894
2006 SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing. The Journal of investigative dermatology 31 16374478
2023 The Formation of NETs and Their Mechanism of Promoting Tumor Metastasis. Journal of oncology 30 36942262
2024 Low-Density Neutrophils and Neutrophil Extracellular Traps (NETs) Are New Inflammatory Players in Heart Failure. The Canadian journal of cardiology 29 38555028
2014 Differentially instructive extracellular protein micro-nets. Journal of the American Chemical Society 29 24825365
2014 Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges. Cancer metastasis reviews 28 24390486
2006 Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein. Clinica chimica acta; international journal of clinical chemistry 27 17140555
2024 TGF-β-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer. Cell death & disease 26 38490994
2012 Knotting the NETs: analyzing histone modifications in neutrophil extracellular traps. Arthritis research & therapy 26 22524286
2024 S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients. Cancer letters 25 39384116
2022 Nets, pulmonary arterial hypertension, and thrombo-inflammation. Journal of molecular medicine (Berlin, Germany) 25 35441845
2012 Gene silencing by H-NS from distal DNA site. Molecular microbiology 25 22924981
2002 The 15-domain serine proteinase inhibitor LEKTI: biochemical properties, genomic organization, and pathophysiological role. European journal of medical research 25 11891144
2025 Neutrophils and NETs in kidney disease. Nature reviews. Nephrology 24 40102634
2023 The involvement of NETs in ANCA-associated vasculitis. Frontiers in immunology 24 37781373
2019 Compound K improves skin barrier function by increasing SPINK5 expression. Journal of ginseng research 24 33192123
2022 Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis. Cellular & molecular biology letters 23 35705923
2018 Interference of transcription across H-NS binding sites and repression by H-NS. Molecular microbiology 23 29424946
2024 Nets in fibrosis: Bridging innate immunity and tissue remodeling. International immunopharmacology 22 38906006
2024 H-NS is a bacterial transposon capture protein. Nature communications 22 39164300
2022 Correlation between Neutrophil Extracellular Traps (NETs) Expression and Primary Graft Dysfunction Following Human Lung Transplantation. Cells 22 36359815