Affinage

NSDHL

Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating · UniProt Q15738

Length
373 aa
Mass
41.9 kDa
Annotated
2026-06-10
35 papers in source corpus 17 papers cited in narrative 17 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

NSDHL is a 3β-hydroxysteroid dehydrogenase that catalyzes a C-4 demethylation step in post-squalene cholesterol biosynthesis, functioning upstream of the sterol isomerase EBP (PMID:10710235); its enzymatic identity is established by complementation of erg26-deficient yeast, where allele-specific complementation defines a functional hierarchy among disease mutations (PMID:14567972, PMID:21129721). The protein traffics through the Golgi to reach ER membranes and the surface of lipid droplets, and disease-associated mutants show altered subcellular distribution (PMID:14506130), with crystal structures defining its coenzyme-binding architecture and a conformational change upon coenzyme binding (PMID:32140747). Loss-of-function mutations cause CHILD syndrome (PMID:10710235), while temperature-sensitive hypomorphic alleles retaining residual activity cause CK syndrome, in which methyl sterol accumulation rather than cholesterol deficiency is the pathogenic driver (PMID:21129721). Through its control of cholesterol synthesis NSDHL is required for Hedgehog/SHH signaling: its deficiency abolishes Ptch1 reporter activity and Ihh cell migration in the placenta (PMID:17028112) and impairs SHH-dependent cerebellar granule precursor proliferation, a defect rescued by exogenous cholesterol while methylsterol accumulation drives cell death (PMID:25652406). NSDHL is also required for placental labyrinth development and trophoblast proliferation, with human NSDHL sufficient to rescue murine null lethality (PMID:15639195, PMID:19880419). In cancer contexts its enzymatic output feeds the LXR-SREBP1 lipogenic axis and activates TGFβ signaling by limiting endosomal degradation of TGFβR2, supporting cancer stem-like maintenance and tumor initiation (PMID:33864166, PMID:39516821), and NSDHL additionally binds STING to promote its ubiquitination-mediated degradation, dampening cGAS-STING-driven IFNβ production (PMID:39290276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 High

    Identified NSDHL as a cholesterol-biosynthetic enzyme and placed it as the genetic cause of CHILD syndrome, establishing both its molecular function and disease relevance.

    Evidence SSCA and genomic sequencing of NSDHL in CHILD syndrome patients with pathway inference relative to EBP

    PMID:10710235

    Open questions at the time
    • Enzymatic activity inferred from pathway position, not directly reconstituted
    • Catalytic mechanism and substrate specificity not biochemically defined
  2. 2003 Medium

    Defined where the protein acts in the cell and that Golgi transit is required to reach the ER, linking trafficking to function.

    Evidence Confocal microscopy of tagged wild-type and mutant murine Nsdhl with Golgi disruption

    PMID:14506130

    Open questions at the time
    • Targeting signals and trafficking machinery not identified
    • Single lab
  3. 2003 High

    Directly confirmed NSDHL as a C-3 sterol dehydrogenase by rescuing erg26-deficient yeast and ranked disease alleles by residual activity.

    Evidence In vivo yeast complementation assay in erg26-deficient cells with multiple Bpa/Str alleles

    PMID:14567972

    Open questions at the time
    • Heterologous yeast system does not measure mammalian kinetics
    • Reaction product not directly characterized
  4. 2005 Medium

    Established that NSDHL is required for placental development, identifying a tissue-level consequence of enzyme loss.

    Evidence Histology and proliferation analysis of Nsdhl mutant mouse embryos across stages

    PMID:15639195

    Open questions at the time
    • Molecular pathway linking sterol defect to trophoblast proliferation not yet defined
  5. 2006 High

    Connected NSDHL loss to impaired Hedgehog signaling, providing a mechanistic link between a metabolic enzyme and a developmental signaling pathway.

    Evidence Ptch1-lacZ reporter and X-linked lacZ cell-autonomy assays in mutant placentas

    PMID:17028112

    Open questions at the time
    • Whether the Hh defect reflects cholesterol loss, sterol accumulation, or both not resolved here
  6. 2009 Medium

    Mapped expression and demonstrated negative selection of NSDHL-deficient cells in liver and brain, showing a cell-intrinsic fitness requirement.

    Evidence Immunohistochemistry across embryonic and postnatal stages in Bpa(1H)/+ mice

    PMID:19631568

    Open questions at the time
    • Molecular basis of negative selection not defined
  7. 2009 High

    Showed the trophoblast lineage is the critical site of NSDHL action and that human NSDHL rescues murine null lethality, confirming functional conservation.

    Evidence Transgenic rescue with human NSDHL and reciprocal-cross placental area dissection

    PMID:19880419

    Open questions at the time
    • Maternal-effect mechanism not mechanistically explained
  8. 2010 High

    Established that hypomorphic NSDHL alleles with residual activity cause CK syndrome and that methyl sterol accumulation, not cholesterol deficiency, is the pathogenic driver.

    Evidence Yeast complementation, temperature-sensitivity assays, and sterol analysis of patient cells and CSF

    PMID:21129721

    Open questions at the time
    • Mechanism of methyl sterol toxicity not defined
  9. 2015 High

    Dissected the SHH cerebellar phenotype to show cholesterol deficiency drives the signaling defect while methylsterol accumulation drives cell death, separating two distinct consequences of enzyme loss.

    Evidence GFAP-cre conditional Nsdhl knockout with in vitro granule precursor proliferation rescue by cholesterol

    PMID:25652406

    Open questions at the time
    • How cholesterol modulates SHH at the molecular level not resolved in this system
  10. 2015 High

    Provided a specific small-molecule (FR171456) and resistance-mutation map confirming NSDHL/Erg26 as a druggable enzyme with defined pathway output.

    Evidence Yeast haploinsufficiency profiling, enzyme inhibition assays, resistance mapping, and sterol measurements

    PMID:26456460

    Open questions at the time
    • Inhibitor selectivity in mammalian tissues not extensively characterized
  11. 2020 High

    Solved NSDHL crystal structures, revealing coenzyme-binding architecture and enabling structure-based inhibitor discovery.

    Evidence X-ray crystallography of two structures with structure-based virtual screening and cell-based EGFR assays

    PMID:32140747

    Open questions at the time
    • Substrate-bound structure not reported
    • Mechanistic link to EGFR activity not biochemically defined
  12. 2021 Medium

    Linked NSDHL enzymatic activity to TGFβ signaling by showing it limits endosomal degradation of TGFβR2 in breast cancer cells.

    Evidence In vivo CRISPR screen, catalytic mutant (Y151X) rescue, and ketoconazole pharmacological rescue of TGFβR2

    PMID:33864166

    Open questions at the time
    • Sterol intermediate responsible for TGFβR2 stabilization not identified
    • Single lab
  13. 2024 Medium

    Identified a non-metabolic role in innate immunity, with NSDHL binding STING and promoting its ubiquitination-mediated degradation to suppress IFNβ.

    Evidence Co-IP, ubiquitination assay, and knockdown/overexpression with IFNβ measurement in cholangiocarcinoma

    PMID:39290276

    Open questions at the time
    • Whether degradation depends on enzymatic activity or scaffolding not resolved
    • Reciprocal validation and E3 ligase not identified
    • Single lab Co-IP
  14. 2024 Medium

    Extended the TGFβ link to cancer stem-cell biology, showing NSDHL knockdown lowers TGFβ secretion, Smad2/3 phosphorylation, and SOX2 to impair tumor initiation.

    Evidence Knockdown in MCF-7 spheroids with RNA-seq, BCSC phenotyping, and orthotopic xenograft initiation assay

    PMID:39516821

    Open questions at the time
    • Mechanism connecting sterol metabolism to TGFβ secretion not biochemically defined
  15. 2026 Medium

    Implicated NSDHL in redox and ER-stress homeostasis, with knockdown triggering lipid peroxidation and ER stress-mediated apoptosis in ovarian cancer.

    Evidence Knockdown with quantitative proteomics, ROS and ER stress markers, ER-specific caspase assay, and xenografts

    PMID:41952197

    Open questions at the time
    • Distinction from ferroptosis depends on marker interpretation
    • Direct molecular trigger of ER stress not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NSDHL's sterol-metabolic output is mechanistically transduced into its signaling roles (Hedgehog, TGFβ, STING/cGAS, ER stress) remains unresolved — whether through specific sterol intermediates, membrane composition, or moonlighting protein interactions.
  • No single sterol intermediate causally tied to a downstream signaling outcome
  • Catalysis-dependent vs. catalysis-independent contributions to STING regulation undefined
  • No structural or biochemical model for NSDHL-partner protein interactions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016787 hydrolase activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1
Partners
STING1TGFBR2

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NSDHL encodes a 3β-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway; loss-of-function mutations in NSDHL cause CHILD syndrome, establishing its enzymatic role upstream of EBP (delta8-delta7 sterol isomerase) in post-squalene cholesterol biosynthesis. SSCA and genomic sequence analysis of NSDHL in CHILD syndrome patients; functional inference from pathway position relative to EBP American journal of medical genetics High 10710235
2003 NSDHL protein localizes to ER membranes and on the surface of lipid droplets; trafficking through the Golgi is necessary for ER membrane localization. Mutant NSDHL alleles show altered subcellular distribution. Confocal microscopy of tagged wild-type and mutant murine Nsdhl proteins; Golgi disruption experiments Human molecular genetics Medium 14506130
2003 Mouse NSDHL protein functionally complements lethality of erg26-deficient Saccharomyces cerevisiae, substantiating its role as a C-3 sterol dehydrogenase. Two striated (Str) alleles function as hypomorphs, while three bare patches (Bpa) and one Str allele provide no complementation. In vivo yeast functional complementation assay in erg26-deficient cells Molecular genetics and metabolism High 14567972
2005 Nsdhl-deficient male embryos die in midgestation (E10.5–13.5) with placental labyrinth thinning, fewer fetal vessels, and decreased proliferation of labyrinth trophoblast cells, indicating NSDHL is required for placental development. Histological and proliferation analysis of Nsdhl mutant mouse embryos at multiple embryonic stages Molecular genetics and metabolism Medium 15639195
2006 Nsdhl deficiency impairs Hedgehog signaling in placental development: Ptch1-lacZ reporter expression is markedly decreased or absent in mutant Nsdhl(Bpa-8H) male placentas, and Indian hedgehog (Ihh)-expressing cells fail to migrate into allantoic mesoderm. Placental defects in heterozygous females are non-cell autonomous. Ptch1-lacZ transgenic reporter assay in Nsdhl mutant and wild-type placentas; X-linked lacZ transgene to assess cell autonomy Human molecular genetics High 17028112
2009 NSDHL is expressed at highest levels in liver, dorsal root ganglia, CNS, retina, adrenal gland, and testis. NSDHL-deficient cells undergo negative selection over the life of the animal in liver and brain, with proportions dropping from ~50% at postnatal day 6 to ~20% by one year of age. Immunohistochemistry in wild-type and heterozygous Bpa(1H)/+ mice across embryonic and postnatal stages Molecular genetics and metabolism Medium 19631568
2009 Expression of Nsdhl specifically in trophoblast lineages (from the maternally inherited allele) has the largest effect on placental area in heterozygous embryos; maternal genotype has an independent smaller effect. Human NSDHL transgene rescues male lethality of the Bpa(1H) null allele. Transgenic rescue with human NSDHL; comparison of placental area at E10.5 using reciprocal cross design to dissect maternal vs. fetal membrane contributions Human molecular genetics High 19880419
2010 Hypomorphic NSDHL mutations (p.Lys232del and p.Arg367SerfsX33) cause CK syndrome with temperature-sensitive protein stability; these mutations complement Erg26-deficient yeast, confirming residual enzymatic activity. Cells and CSF from CKS patients have increased methyl sterol levels, implicating methyl sterol accumulation (not cholesterol deficiency) as pathogenic. Yeast complementation assay; temperature-sensitivity assays; sterol analysis of patient cells and CSF American journal of human genetics High 21129721
2015 Conditional ablation of Nsdhl in radial glia (GFAP-cre) causes defective SHH signaling, impairing cerebellar granule cell precursor proliferation; this defect is almost completely rescued by exogenous cholesterol supplementation in vitro, while methylsterol accumulation above the block is associated with increased cell death. Conditional Nsdhl knockout mice (Nsdhl(tm1.1Hrm)/GFAP-cre); in vitro granule cell precursor proliferation assay with cholesterol supplementation; sterol measurements Human molecular genetics High 25652406
2015 FR171456 specifically inhibits NSDHL (human) and its yeast ortholog Erg26p; multiple ERG26 mutations confer resistance to FR171456 in growth and enzyme assays, and the compound significantly alters cholesterol pathway intermediate levels in human and yeast cells. Genome-wide yeast haploinsufficiency profiling; enzyme inhibition assays; resistance mutation mapping; sterol intermediate measurements in human cells Nature communications High 26456460
2020 X-ray crystal structures of human NSDHL reveal detailed coenzyme-binding site architecture and a unique conformational change upon coenzyme binding; structure-based virtual screening identified a novel inhibitor that suppresses EGFR activity in cancer cells. X-ray crystallography (two structures); structure-based virtual screening; biochemical inhibitor evaluation; cell-based EGFR activity assay Cellular and molecular life sciences : CMLS High 32140747
2020 NSDHL knockdown attenuates adipogenesis in 3T3-L1 cells, associated with downregulation of the LXR-SREBP1 signaling pathway and reduced PPARγ expression. NSDHL knockdown in 3T3-L1 preadipocytes; qRT-PCR; lipid accumulation assay Bioscience, biotechnology, and biochemistry Low 31985358
2021 NSDHL activates TGFβ signaling by inhibiting endosomal degradation of TGFβR2 in triple-negative breast cancer cells; this function depends on NSDHL enzymatic activity (Y151X inactive mutant fails to rescue migration or TGFβR2 expression). Blocking upstream NSDHL metabolism with ketoconazole rescues TGFβR2 degradation. CRISPR screen in vivo; NSDHL knockdown/overexpression; inactive mutant (Y151X) rescue assay; ketoconazole treatment; TGFβR2 protein expression analysis Breast cancer research and treatment Medium 33864166
2023 IFN-γ decreases NSDHL expression in HCC, which activates SREBP1 and promotes TGF-β1 production, reducing T cell cytotoxicity and enhancing Treg infiltration. Regorafenib reverses ICI resistance by restoring NSDHL/SREBP1/TGF-β1 axis. In vitro NSDHL knockdown/overexpression; SREBP1 and TGF-β1 expression assays; T cell co-culture; Treg infiltration analysis; regorafenib treatment Biomedicine & pharmacotherapy Low 36669362
2024 NSDHL binds to STING and facilitates its degradation via ubiquitination, thereby inhibiting the cGAS-STING signaling pathway and reducing IFNβ synthesis in cholangiocarcinoma. Co-IP (NSDHL-STING interaction); overexpression/knockdown experiments; ubiquitination assay; IFNβ measurement Heliyon Medium 39290276
2024 NSDHL knockdown in MCF-7 spheroids suppresses TGF-β1 and TGF-β3 secretion, reduces Smad2/3 phosphorylation, and decreases SOX2 expression, impairing breast cancer stem-like cell maintenance and tumor-initiating capacity. NSDHL knockdown in MCF-7 spheroids; RNA sequencing; BCSC phenotype assays (CD44/CD24, ALDH); orthotopic xenograft tumor initiation assay BMC cancer Medium 39516821
2026 NSDHL knockdown in ovarian cancer cells triggers lipid peroxidation and ER stress-mediated apoptosis (not ferroptosis), with upregulation of ACSL4 and downregulation of ACSL3, reducing intracellular iron levels; NSDHL depletion suppresses tumor growth in xenografts. NSDHL knockdown; quantitative proteomic profiling; ROS measurement; ER stress marker analysis; ER-specific caspase activation assay; xenograft tumor model Biology direct Medium 41952197

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. American journal of medical genetics 191 10710235
2003 NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. Human molecular genetics 84 14506130
2010 Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. American journal of human genetics 44 21129721
2002 A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. Journal of the American Academy of Dermatology 38 11907515
2021 NSDHL promotes triple-negative breast cancer metastasis through the TGFβ signaling pathway and cholesterol biosynthesis. Breast cancer research and treatment 33 33864166
2015 Analysis of hedgehog signaling in cerebellar granule cell precursors in a conditional Nsdhl allele demonstrates an essential role for cholesterol in postnatal CNS development. Human molecular genetics 29 25652406
2003 Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. American journal of medical genetics. Part A 28 12966526
2018 RNA-Seq analysis reveals a negative role of MSMO1 with a synergized NSDHL expression during adipogenesis of 3T3-L1. Bioscience, biotechnology, and biochemistry 23 30582412
2006 Analysis of Nsdhl-deficient embryos reveals a role for Hedgehog signaling in early placental development. Human molecular genetics 21 17028112
2005 Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme. Molecular genetics and metabolism 20 15639195
2023 Regorafenib enhances anti-tumor efficacy of immune checkpoint inhibitor by regulating IFN-γ/NSDHL/SREBP1/TGF-β1 axis in hepatocellular carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 36669362
2005 CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene. Dermatology (Basel, Switzerland) 18 16088165
2003 Identification of two novel mutations in the murine Nsdhl sterol dehydrogenase gene and development of a functional complementation assay in yeast. Molecular genetics and metabolism 17 14567972
2017 A Large Deletion in the NSDHL Gene in Labrador Retrievers with a Congenital Cornification Disorder. G3 (Bethesda, Md.) 16 28739597
2009 Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa(1H)/+ mouse. Molecular genetics and metabolism 16 19631568
2020 Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity. Cellular and molecular life sciences : CMLS 14 32140747
2015 FR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p. Nature communications 13 26456460
2009 CHILD syndrome: the NSDHL gene and its role in CHILD syndrome, a rare hereditary disorder. Journal of the European Academy of Dermatology and Venereology : JEADV 13 19906044
2019 Identification of NSDHL mutations associated with CHILD syndrome in oral verruciform xanthoma. Oral surgery, oral medicine, oral pathology and oral radiology 10 31078502
2019 A missense variant in the NSDHL gene in a Chihuahua with a congenital cornification disorder resembling inflammatory linear verrucous epidermal nevi. Animal genetics 8 31571289
2022 Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review. Molecular genetics & genomic medicine 7 36504312
2020 Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report. BMC medical genetics 7 32819291
2015 A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome. American journal of medical genetics. Part A 7 25900314
2018 NSDHL-containing duplication at Xq28 in a male patient with autism spectrum disorder: a case report. BMC medical genetics 6 30376821
2024 NSDHL contributes to breast cancer stem-like cell maintenance and tumor-initiating capacity through TGF-β/Smad signaling pathway in MCF-7 tumor spheroid. BMC cancer 5 39516821
2022 CPSF1 positively regulates NSDHL by alternative polyadenylation and promotes gastric cancer progression. American journal of cancer research 5 36381317
2020 Suppression of NSDHL attenuates adipogenesis with a downregulation of LXR-SREBP1 pathway in 3T3-L1 cells. Bioscience, biotechnology, and biochemistry 5 31985358
2020 Novel NSDHL gene variant for congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome. BMJ case reports 5 33139364
2020 NSDHL Frameshift Deletion in a Mixed Breed Dog with Progressive Epidermal Nevi. Genes 5 33143176
2018 Genetic variant in the NSDHL gene in a cat with multiple congenital lesions resembling inflammatory linear verrucous epidermal nevi. Veterinary dermatology 5 30474267
2013 Identification of a novel polymorphism in X-linked sterol-4-alpha-carboxylate 3-dehydrogenase (Nsdhl) associated with reduced high-density lipoprotein cholesterol levels in I/LnJ mice. G3 (Bethesda, Md.) 4 23979938
2021 A novel NSDHL variant in CHILD syndrome with gastrointestinal manifestations and localized skin involvement. Molecular genetics & genomic medicine 3 34957706
2009 Significant contributions of the extraembryonic membranes and maternal genotype to the placental pathology in heterozygous Nsdhl deficient female embryos. Human molecular genetics 3 19880419
2024 NSDHL promotes the degradation of sting in cholangiocarcinoma. Heliyon 1 39290276
2026 NSDHL as a regulator of lipid peroxidation and ER stress-mediated apoptosis in ovarian cancer. Biology direct 0 41952197

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