Affinage

NCSTN

Nicastrin · UniProt Q92542

Length
709 aa
Mass
78.4 kDa
Annotated
2026-06-10
22 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCSTN encodes nicastrin, a subunit of the γ-secretase complex whose principal characterized function is to drive regulated intramembrane proteolysis of Notch receptors, coupling nicastrin dosage to Notch-dependent differentiation and inflammatory programs (PMID:39719647). In skin, NCSTN loss-of-function lowers nicastrin and reduces the Notch intracellular domain (NICD) together with downstream Hes1, and this Notch1–Hes1 axis is regulated by NCSTN across skin, brain, and liver (PMID:35843211, PMID:39719647). Epidermis-specific deletion of Ncstn in mice produces hair-follicle hyperkeratosis with reduced hair-cortex cytokeratin and trichohyalin, and triggers an early, IL-36α-led inflammatory cascade that precedes upregulation of TNF-α, IL-23A, IL-1β, and TLR4 (PMID:31884525, PMID:35843211). NCSTN haploinsufficiency in hidradenitis suppurativa/acne inversa arises through several convergent loss-of-function routes: a nonsense mutation that lowers nicastrin mRNA and protein in skin and keratinocytes (PMID:26224166), nonsense-mediated decay that also depletes other γ-secretase subunits and is correctable by the readthrough agent gentamicin (PMID:37665193), and miR-155-mediated 3'UTR suppression accentuated by a binding-site deletion (PMID:31938294). NCSTN also gates Notch3–Hes1 signaling to control airway basal-cell differentiation into ciliated cells (PMID:42105283). In hepatocellular carcinoma, by contrast, NCSTN cleaves Notch1 to activate AKT signaling, phosphorylating GSK-3β to stabilize β-catenin, promote its nuclear translocation, and upregulate Zeb1-driven EMT; this axis is modulated by direct binding of LRP1B to nicastrin (PMID:32631394, PMID:37492741).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2015 Medium

    Established that a patient nonsense mutation produces true haploinsufficiency rather than a non-functional full-length protein, anchoring NCSTN dosage as the disease-relevant variable in hidradenitis suppurativa.

    Evidence qPCR and Western blot on patient skin compartments and primary keratinocytes/fibroblasts

    PMID:26224166

    Open questions at the time
    • Does not define how reduced nicastrin alters γ-secretase activity or Notch signaling in this tissue
    • Single patient genotype
  2. 2018 Medium

    Identified a post-transcriptional loss-of-function route, showing miR-155 represses NCSTN via its 3'UTR and that a binding-site deletion deepens repression, broadening disease mechanisms beyond coding mutations.

    Evidence Dual-luciferase 3'UTR reporter with mutant construct, qRT-PCR, Western blot

    PMID:31938294

    Open questions at the time
    • No in vivo demonstration that miR-155 drives disease
    • Downstream Notch consequences not measured here
  3. 2019 High

    Demonstrated causally that epidermal Ncstn loss is sufficient to produce follicular hyperkeratosis and a defined inflammatory sequence led by IL-36α, linking nicastrin deficiency to the inflammatory phenotype.

    Evidence K5-Cre conditional knockout mice, RNA-seq, qRT-PCR

    PMID:31884525

    Open questions at the time
    • Does not establish whether IL-36α induction is Notch-dependent
    • Trigger linking nicastrin loss to IL-36α not defined
  4. 2020 Medium

    Defined a gain-of-function oncogenic role in HCC, mapping NCSTN through Notch1 cleavage to AKT/GSK-3β/β-catenin and Zeb1-driven EMT, contrasting with the loss-of-function skin disease axis.

    Evidence Co-IP, subcellular fractionation, Notch/AKT inhibitor epistasis, xenografts

    PMID:32631394

    Open questions at the time
    • Single tumor type
    • Direct enzymatic substrate role versus complex-level effect not separated
  5. 2022 Medium

    Connected NCSTN to an upstream regulator and to its hair-follicle differentiation output, with LRP1B binding controlling nicastrin levels/PI3K-AKT in HCC and NCSTN mutation reducing NICD, trichohyalin and hair-cortex cytokeratin in mice.

    Evidence Co-IP plus knockdown with PI3K/AKT readouts (HCC); WB, IHC, H&E, TEM in NCSTN-mutant mice

    PMID:35843211 PMID:37492741

    Open questions at the time
    • LRP1B–nicastrin interaction studied only in HCC, not skin
    • Whether NICD loss directly causes the structural follicle defect not proven
  6. 2023 Medium

    Mechanistically resolved the haploinsufficiency route as nonsense-mediated decay that co-depletes other γ-secretase subunits, and provided a pharmacological correction by readthrough.

    Evidence Whole exome sequencing, patient outer root sheath cells, gentamicin readthrough rescue

    PMID:37665193

    Open questions at the time
    • Rescue shown at protein level only, not for disease phenotype
    • Single mutation/patient context
  7. 2024 Medium

    Generalized the NCSTN→Notch1→Hes1 regulatory axis beyond skin, showing coordinate reduction of nicastrin, NICD1 and Hes1 across skin, brain, and liver.

    Evidence CRISPR/Cas9 NCSTN knockout mice, qRT-PCR, immunohistochemistry

    PMID:39719647

    Open questions at the time
    • Functional consequences in brain and liver not characterized
    • Expression-level changes only
  8. 2026 Medium

    Extended NCSTN's developmental role to airway epithelium, placing it upstream of Notch3–Hes1 in suppressing basal-cell differentiation into ciliated cells, and added JAK/STAT as a candidate inflammatory effector of skin NCSTN loss.

    Evidence Reciprocal lentiviral overexpression/knockdown in tracheal basal cells at ALI (RT-qPCR, WB); tamoxifen-induced conditional KO skin with JAK isoform IHC

    PMID:41670523 PMID:42105283

    Open questions at the time
    • JAK/STAT link is expression-only by single-method IHC (Low confidence) with no functional test
    • Whether Notch1 versus Notch3 engagement is tissue-specific not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single quantitative reduction in nicastrin selectively produces inflammatory follicular disease in skin yet tumor-promoting EMT in HCC, and the molecular trigger linking nicastrin/Notch loss to IL-36α and JAK/STAT induction, remain unresolved.
  • No reconciliation of loss-of-function versus gain-of-function context dependence
  • IL-36α induction mechanism downstream of nicastrin not defined
  • No structural/biochemical accounting of how nicastrin dosage tunes γ-secretase output in these tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
LRP1BNOTCH1NOTCH3
Complex memberships
γ-secretase complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 NCSTN promotes HCC cell growth and metastasis by cleaving Notch1, which activates AKT and increases AKT/GSK-3β phosphorylation, thereby decreasing the GSK-3β/β-catenin complex, inhibiting β-catenin degradation, promoting nuclear translocation of β-catenin, and upregulating the transcription of Zeb1 to induce EMT. Notch and AKT inhibitor pharmacological dissection, co-immunoprecipitation, subcellular protein fractionation, immunofluorescence, in vitro cell assays, and in vivo xenograft models Journal of experimental & clinical cancer research : CR Medium 32631394
2022 LRP1B directly binds to NCSTN protein and affects its expression level, thereby regulating the PI3K/AKT signaling pathway in HCC cells. Co-immunoprecipitation (Co-IP) and in vitro/in vivo knockdown experiments with pathway readouts Genes & diseases Medium 37492741
2015 Haploinsufficiency of NCSTN caused by a nonsense mutation (c.1258C>T, p.Q420X) results in significantly reduced nicastrin mRNA and protein levels in skin (whole skin, epidermis, dermis) and cultured keratinocytes and fibroblasts from hidradenitis suppurativa patients. Real-time quantitative PCR and Western blotting on patient-derived skin samples and primary cell cultures Clinical and experimental dermatology Medium 26224166
2019 Keratin 5-Cre-driven epidermis-specific knockout of Ncstn in mice causes hyperkeratosis of hair follicles, inflammation, and markedly increased IL-36α expression starting from postnatal day 0, preceding upregulation of TNF-α, IL-23A, IL-1β, and TLR4; Sprr2 family members are also upregulated. Conditional knockout mouse model (K5-Cre), RNA-seq, and qRT-PCR Frontiers of medicine High 31884525
2022 NCSTN mutation in C57BL/6 mice downregulates nicastrin protein, NICD (Notch intracellular domain), hair cortex cytokeratin, and trichohyalin, and causes abnormal hair follicle structure, leading to HS-like skin lesions. Western blot, immunohistochemistry, hematoxylin-eosin staining, and transmission electron microscopy in NCSTN-mutant mice Dermatology (Basel, Switzerland) Medium 35843211
2024 NCSTN knockout mice show reduced expression of nicastrin, NICD1, and Hes1 in skin, brain, and liver tissues, demonstrating that NCSTN regulates the Notch1-Hes1 signaling pathway in multiple organs. CRISPR/Cas9-mediated NCSTN knockout mice, qRT-PCR, and immunohistochemistry European journal of medical research Medium 39719647
2026 NCSTN overexpression suppresses airway epithelial basal cell differentiation into ciliated cells and activates Notch3/Hes1 signaling; NCSTN knockdown attenuates CSE-induced reduction in ciliated cell differentiation and inhibits Notch3 activation, placing NCSTN upstream of Notch3-Hes1 in the regulation of ciliated cell differentiation. Lentiviral overexpression and knockdown in mouse tracheal epithelial basal cells at air-liquid interface, RT-qPCR, and Western blotting Experimental lung research Medium 42105283
2018 miR-155 downregulates NCSTN expression by binding to the NCSTN 3'UTR; a deletion mutation (c.2584-2585del CA) at the miR-155 binding site in the NCSTN 3'UTR further reduces NCSTN protein levels, representing a loss-of-function mechanism in acne inversa. Dual-luciferase reporter assay with wild-type and mutant NCSTN 3'UTR constructs, qRT-PCR, and Western blot International journal of clinical and experimental pathology Medium 31938294
2023 A nonsense mutation in NCSTN leads to a premature stop codon, activates nonsense-mediated mRNA decay, and causes NCSTN haploinsufficiency in affected individuals; this haploinsufficiency also reduces protein levels of other γ-secretase complex subunits. Treatment with gentamicin (a readthrough agent) corrected NCSTN levels in patient-derived outer root sheath cells. Whole exome sequencing, outer root sheath cell isolation from patient hair follicles, gentamicin readthrough experiment, protein quantification Experimental dermatology Medium 37665193
2026 In NCSTN conditional knockout mouse skin, JAK1, JAK3, and TYK2 are upregulated in the epidermis, and JAK2 is upregulated in the dermis, implicating the JAK/STAT signaling pathway downstream of NCSTN loss. Tamoxifen-induced conditional NCSTN knockout mice, immunohistochemistry with ImageJ quantification Clinical laboratory Low 41670523

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance. Genes & diseases 52 37492741
2013 A novel splice site mutation in NCSTN underlies a Japanese family with hidradenitis suppurativa. The British journal of dermatology 44 22834455
2020 NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner. Journal of experimental & clinical cancer research : CR 40 32631394
2012 Two novel mutations of the NCSTN gene in Chinese familial acne inverse. Journal of the European Academy of Dermatology and Venereology : JEADV 36 22759192
2019 Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression. Frontiers of medicine 22 31884525
2015 Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22 25953768
2018 A novel NCSTN gene mutation in a Chinese family with acne inversa. Molecular genetics and genomics : MGG 15 30030622
2020 Novel Mutation of the NCSTN Gene Identified in a Chinese Acne Inversa Family. Annals of dermatology 11 33911744
2023 An Updated Mutation Spectrum of the γ-Secretase Complex: Novel NCSTN Gene Mutation in an Indian Family with Hidradenitis Suppurativa and Acne Conglobata. Indian journal of dermatology 10 37275792
2015 A strategy focused on MAPT, APP, NCSTN and BACE1 to build blood classifiers for Alzheimer's disease. Journal of theoretical biology 9 25863267
2015 Haploinsufficiency caused by a nonsense mutation in NCSTN underlying hidradenitis suppurativa in a Chinese family. Clinical and experimental dermatology 9 26224166
2023 A loss-of-function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa. Experimental dermatology 7 37665193
2022 Effects of NCSTN Mutation on Hair Follicle Components in Mice. Dermatology (Basel, Switzerland) 6 35843211
2018 hsa-miR-155 targeted NCSTN 3'UTR mutation promotes the pathogenesis and development of acne inversa. International journal of clinical and experimental pathology 6 31938294
2022 A Novel NCSTN Mutation in a Three-Generation Chinese Family with Hidradenitis Suppurative. Journal of healthcare engineering 5 35368949
2023 Discovery and Potential Functional Characterization of Long Noncoding RNAs Associated with Familial Acne Inversa with NCSTN Mutation. Dermatology (Basel, Switzerland) 3 37490873
2020 The combination between NCSTN gene copy number variation and growth traits in Chinese cattle. Animal biotechnology 3 32208881
2024 Expression of nicastrin, NICD1, and Hes1 in NCSTN knockout mice: implications for hidradenitis suppurativa, Alzheimer's, and liver cancer. European journal of medical research 2 39719647
2026 Immunolocalization and Expression of JAK/STAT Signaling Molecules in the Skin of NCSTN Knockout Mouse. Clinical laboratory 0 41670523
2026 Mechanistic study on the role of NCSTN in regulating the differentiation of airway epithelial basal cells into ciliated cells following CSE exposure. Experimental lung research 0 42105283
2025 Pathogenic variants in PSENEN and NCSTN genes cause 'follicular' Dowling-Degos disease: Report of five unrelated Indian families. Indian journal of dermatology, venereology and leprology 0 40357971
2023 Retracted: A Novel NCSTN Mutation in a Three-Generation Chinese Family with Hidradenitis Suppurative. Journal of healthcare engineering 0 37662678

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