id: Q15738
gene_symbol: NSDHL
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  NSDHL (NAD(P)-dependent steroid dehydrogenase-like protein) is the
  sterol-4-alpha-carboxylate 3-dehydrogenase (decarboxylating) (EC 1.1.1.170) of
  the C4-demethylation machinery in post-squalene cholesterol/sterol biosynthesis.
  Acting after the sterol C4-methyl oxidase MSMO1 has oxidised a C4 methyl group to
  a carboxylate, NSDHL catalyses the NAD(P)+-dependent 3-beta-hydroxysteroid
  dehydrogenation and oxidative decarboxylation of the 4-alpha-carboxysterol,
  producing a 3-oxo (3-keto) sterol plus CO2; a 3-ketosteroid reductase (HSD17B7)
  then reduces the ketone back to the 3-beta-ol. Two iterations of this cycle remove
  both C4 methyl groups (e.g. converting 4,4-dimethyl sterol intermediates toward
  zymosterol/zymostenol). NSDHL is a single-pass endoplasmic reticulum membrane
  protein belonging to the 3-beta-hydroxysteroid dehydrogenase (short-chain
  dehydrogenase/reductase) family, uses an NAD(P)-binding Rossmann fold, functions
  as a homodimer, and is also found on lipid droplets. In humans, loss-of-function
  or hypomorphic mutations cause the X-linked cholesterol-biosynthesis disorders
  CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb
  Defects; X-linked dominant, male-lethal) and CK syndrome (X-linked recessive
  intellectual disability with cortical malformation).
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that NSDHL is active in the endoplasmic
      reticulum. This is consistent with all experimental localization data
      (HPA IDA, LIFEdb IDA) and with the enzyme's role in the ER-membrane sterol
      C4-demethylation complex.
    action: ACCEPT
    reason: >-
      Correct compartment for this sterol-biosynthetic enzyme; corroborated by IDA
      evidence and by the UniProt subcellular location. ER (membrane) is the
      established site of action.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) inference of the general oxidoreductase activity class.
      This is the correct parent for NSDHL's NAD(P)+-dependent 3-beta-hydroxysteroid
      dehydrogenase/C4-decarboxylase reaction, in which the 3-beta-OH group is
      oxidised with NAD(P)+ as acceptor.
    action: ACCEPT
    reason: >-
      Accurate but general; the specific activity is captured by GO:0000252. Retained
      as a correct (non-core) grouping term.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "NAD(P)(+)-dependent oxidative decarboxylation"
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) inference that NSDHL is involved in cholesterol metabolism.
      NSDHL is a committed post-squalene cholesterol-biosynthetic enzyme; sterol
      analyses of Bpa (Nsdhl-mutant) mice support a role in cholesterol biosynthesis.
    action: ACCEPT
    reason: >-
      Correct but broader than the specific biosynthetic role. Retained as a valid
      parent process; the precise core process is cholesterol biosynthetic process
      (GO:0006695).
    supported_by:
    - reference_id: PMID:10369263
      supporting_text: "Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis"
- term:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/Rhea/EC) assertion of the core molecular function:
      NAD(P)+-dependent 3-beta-hydroxysteroid dehydrogenase / C4-decarboxylase
      activity (EC 1.1.1.170), mapped from RHEA:33447/34771 and EC:1.1.1.170.
    action: ACCEPT
    reason: >-
      This is NSDHL's defining catalytic activity and is independently supported by
      EXP, ISS (from mouse ortholog Q9R1J0) and TAS evidence. Correct and specific.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "a 3beta-hydroxysteroid-4alpha-carboxylate + NADP(+) = a 3- oxosteroid + CO2 + NADPH"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated (ARBA / UniProtKB-SubCell) assertion of ER membrane localization.
      NSDHL is a single-pass ER membrane protein with a C-terminal ER-retention
      motif, experimentally localized to the ER membrane (PMID:21129721).
    action: ACCEPT
    reason: >-
      Correct and experimentally corroborated (EXP, IC). Represents the precise site
      of the enzyme in the ER-membrane C4-demethylation complex.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated (ARBA / UniProtKB-SubCell) assertion of lipid droplet localization,
      transferred from the mouse ortholog. NSDHL also localizes to lipid droplets in
      addition to the ER membrane; consistent with independent IDA evidence
      (PMID:21498505, PMID:14741744, HPA).
    action: ACCEPT
    reason: >-
      Well-supported secondary localization; lipid droplets are contiguous with the
      ER and host several sterol/lipid enzymes. Non-core relative to the ER site of
      catalysis.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Lipid droplet"
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO (IPR002225, 3-beta-HSD/estradiol dehydrogenase family) assertion of
      involvement in steroid biosynthesis. Sterols are steroids, so this is correct
      but broad relative to the cholesterol biosynthetic process.
    action: ACCEPT
    reason: >-
      Accurate parent process. Retained as a valid (non-core) grouping term; the
      specific process is cholesterol biosynthetic process (GO:0006695).
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "C4 methyl groups of 4-alpha-carboxysterols in post-squalene"
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP
      as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IPR002225) assertion of the general oxidoreductase activity class.
      Same correct-but-general molecular function as the IBA annotation to this term;
      the specific activity is GO:0000252.
    action: ACCEPT
    reason: >-
      Accurate parent MF term consistent with the NAD(P)+-dependent CH-OH
      dehydrogenation NSDHL performs. Retained as a correct (non-core) grouping term.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "NAD(P)(+)-dependent oxidative decarboxylation"
- term:
    id: GO:0102175
    label: 3-beta-hydroxysteroid dehydrogenase (NAD+)/C4-decarboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Rhea-based (RHEA:34775) assertion of the NAD+-specific form of NSDHL's core
      3-beta-hydroxysteroid dehydrogenase/C4-decarboxylase activity. NSDHL uses both
      NAD+ and NADP+; multiple NAD+ catalytic reactions are recorded in UniProt.
    action: ACCEPT
    reason: >-
      Correct, specific molecular function reflecting the NAD+ cofactor variant of
      EC 1.1.1.170. Supported additionally by ISS from the mouse ortholog.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3- oxosteroid + CO2 + NADH"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      High-throughput binary interaction (yeast two-hybrid) from the HuRI reference
      interactome map; the recorded partner (UniProtKB:Q8TEB9, RHBDD1) is one of the
      IntAct binary interactions listed in UniProt. This 'protein binding' term is
      uninformative about NSDHL's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidance, bare 'protein binding' from a systematic interactome
      screen conveys no specific molecular function and is not part of the core
      catalytic role; it is retained but flagged as over-annotation rather than
      removed (the underlying IPI evidence is real).
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: "reference interactome map of human binary protein interactions, or 'HuRI'"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome-mapping interaction (partner UniProtKB:P54253,
      ATXN1) from a neurodegenerative-disease interactome screen; also captured among
      the IntAct binary interactions in UniProt. Again an uninformative 'protein
      binding' assertion.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare 'protein binding' from a large-scale interactome study does not describe a
      specific molecular function and is not core; flagged as over-annotation per
      policy rather than removed.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: "Interactome maps are valuable resources to elucidate protein function"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Ensembl-Compara orthology transfer (from mouse Q9R1J0) of endoplasmic reticulum
      localization. Consistent with all experimental and phylogenetic evidence for
      ER localization of NSDHL.
    action: ACCEPT
    reason: >-
      Correct compartment, corroborated by IDA and IBA annotations to the same term.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807047
  qualifier: involved_in
  review:
    summary: >-
      Reactome-asserted involvement in cholesterol biosynthesis (Bloch pathway via
      desmosterol). NSDHL performs the C4-decarboxylation steps that convert
      4,4-dimethyl/4-monomethyl sterol intermediates toward zymosterol and onward to
      cholesterol.
    action: ACCEPT
    reason: >-
      This is the precise core biological process for NSDHL. Both the Bloch and
      Kandutsch-Russell routes share the NSDHL-catalyzed C4-demethylation steps.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "post-squalene cholesterol biosynthesis"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807062
  qualifier: involved_in
  review:
    summary: >-
      Reactome-asserted involvement in cholesterol biosynthesis (Kandutsch-Russell
      pathway via lathosterol/zymostenol). NSDHL's C4-demethylation reactions are
      shared between the Bloch and Kandutsch-Russell routes.
    action: ACCEPT
    reason: >-
      Correct core biological process, identical to the Bloch-pathway annotation; the
      two Reactome pathway objects reflect the branched post-zymosterol routes.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "post-squalene cholesterol biosynthesis"
- term:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  evidence_type: EXP
  original_reference_id: PMID:10369263
  qualifier: enables
  review:
    summary: >-
      Experimental annotation (via Reactome) of the core C4-decarboxylase activity.
      Liu et al. identified Nsdhl as encoding an NAD(P)H steroid dehydrogenase-like
      protein and showed by sterol profiling of Bpa mutant mice a role in cholesterol
      biosynthesis, establishing the enzyme's function in sterol C4-demethylation.
    action: ACCEPT
    reason: >-
      Core molecular function with experimental support in the mammalian ortholog;
      duplicate GO term (with IEA/ISS/TAS) is expected and appropriate.
    supported_by:
    - reference_id: PMID:10369263
      supporting_text: "encoding an NAD(P)H steroid dehydrogenase-like protein"
- term:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194642
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for the C4-decarboxylase activity in the reaction converting
      4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol to
      4-methylcholesta-8(9),24-dien-3-one + CO2 + NADH, catalyzed by NSDHL in the ER.
    action: ACCEPT
    reason: >-
      Correct, specific representation of NSDHL's core catalytic activity within a
      defined cholesterol-biosynthesis reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-194642
      supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- term:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194718
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for the C4-decarboxylase activity in the reaction converting
      4-carboxycholesta-8(9),24-dien-3beta-ol to zymosterone + CO2 + NADH, catalyzed
      by NSDHL in the ER.
    action: ACCEPT
    reason: >-
      Correct, specific representation of NSDHL's core activity in another
      cholesterol-biosynthesis C4-decarboxylation step.
    supported_by:
    - reference_id: Reactome:R-HSA-194718
      supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct assay (immunofluorescence, Human Protein Atlas) localizing NSDHL to the
      endoplasmic reticulum. Consistent with the enzyme's established ER-membrane
      residence.
    action: ACCEPT
    reason: >-
      Experimental (IDA) support for the correct compartment.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct assay (immunofluorescence, Human Protein Atlas) localizing NSDHL to lipid
      droplets, consistent with the UniProt lipid-droplet annotation and independent
      lipid-droplet proteomic detections.
    action: ACCEPT
    reason: >-
      Experimental support for a genuine secondary localization; non-core relative to
      the ER site of catalysis.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Lipid droplet"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IC
  original_reference_id: PMID:10710235
  qualifier: is_active_in
  review:
    summary: >-
      Curator inference (IC) that NSDHL is active in the ER membrane, based on its
      3-beta-hydroxysteroid dehydrogenase activity in the cholesterol-biosynthetic
      pathway. NSDHL is a single-pass ER-membrane enzyme, so the site of catalysis is
      the ER membrane.
    action: ACCEPT
    reason: >-
      Correct site-of-action for this membrane-embedded sterol enzyme; consistent with
      the EXP localization (PMID:21129721) and UniProt.
    supported_by:
    - reference_id: PMID:10710235
      supporting_text: "a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway"
- term:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of the core C4-decarboxylase activity from the
      mouse ortholog (UniProtKB:Q9R1J0), where the reaction and kinetics are
      characterized. Fully consistent with the EXP/IEA/TAS annotations to the same term.
    action: ACCEPT
    reason: >-
      Well-justified orthology-based assignment of NSDHL's defining molecular function.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "EC=1.1.1.170 {ECO:0000250|UniProtKB:Q9R1J0}"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:21129721
  qualifier: located_in
  review:
    summary: >-
      Experimental determination of ER-membrane localization for NSDHL, from the CK
      syndrome study that characterized temperature-sensitive hypomorphic alleles and
      subcellular location; this is the primary experimental basis for the UniProt ER
      membrane annotation.
    action: ACCEPT
    reason: >-
      Direct experimental support (EXP) for the enzyme's site in the ER membrane.
    supported_by:
    - reference_id: PMID:21129721
      supporting_text: "encodes an enzyme in the cholesterol biosynthesis pathway"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of lipid-droplet localization from the mouse
      ortholog (UniProtKB:Q9R1J0). Corroborated by human IDA lipid-droplet evidence.
    action: ACCEPT
    reason: >-
      Consistent with experimental lipid-droplet localization in human cells; a valid
      non-core localization.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Lipid droplet {ECO:0000250|UniProtKB:Q9R1J0}"
- term:
    id: GO:0102175
    label: 3-beta-hydroxysteroid dehydrogenase (NAD+)/C4-decarboxylase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity (ISS) transfer of the NAD+-specific C4-decarboxylase activity
      from the mouse ortholog (UniProtKB:Q9R1J0). Matches the Rhea-based IEA to the same
      term.
    action: ACCEPT
    reason: >-
      Correct, specific NAD+ variant of NSDHL's core molecular function; orthology
      support is appropriate.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3- oxosteroid + CO2 + NADH"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21498505
  qualifier: located_in
  review:
    summary: >-
      NSDHL was detected on lipid droplets in a study of LPCAT1/2 lipid-droplet
      localization; lipid droplets are shown to be sites of local lipid metabolism and
      host multiple ER-derived lipid enzymes. Supports the lipid-droplet localization
      of NSDHL.
    action: ACCEPT
    reason: >-
      Direct-assay support for a genuine secondary localization; non-core relative to
      catalysis in the ER membrane.
    supported_by:
    - reference_id: PMID:21498505
      supporting_text: "both enzymes additionally localize to lipid droplets"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:14741744
  qualifier: located_in
  review:
    summary: >-
      NSDHL was identified in the lipid-droplet-enriched proteome of human HuH7
      hepatocytes, a proteomic study that catalogued lipid-metabolizing enzymes
      enriched on lipid droplets. Provides proteomic evidence for lipid-droplet
      association.
    action: ACCEPT
    reason: >-
      Direct-assay (proteomic) support for the lipid-droplet localization; consistent
      with other IDA/ISS evidence. Non-core.
    supported_by:
    - reference_id: PMID:14741744
      supporting_text: "a fraction enriched with lipid droplets was isolated"
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: >-
      Direct localization (LIFEdb, GFP-fusion in living cells) of NSDHL to the
      endoplasmic reticulum. Consistent with all other ER evidence.
    action: ACCEPT
    reason: >-
      Experimental support for the correct compartment.
    supported_by:
    - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194642
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing the NSDHL-catalyzed decarboxylation reaction to the ER
      membrane. Consistent with EXP/IC/IDA evidence for ER-membrane residence.
    action: ACCEPT
    reason: >-
      Correct localization to the site of the C4-demethylation complex.
    supported_by:
    - reference_id: Reactome:R-HSA-194642
      supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194718
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing another NSDHL decarboxylation reaction (to zymosterone)
      to the ER membrane. Duplicate of the correct ER-membrane localization.
    action: ACCEPT
    reason: >-
      Correct localization; duplicate ER-membrane TAS from a related Reactome reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-194718
      supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9945787
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing the NSDHL reaction converting
      4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol to 5alpha-cholest-8-en-3-one to the
      ER membrane.
    action: ACCEPT
    reason: >-
      Correct ER-membrane localization for a specific NSDHL decarboxylation step.
    supported_by:
    - reference_id: Reactome:R-HSA-9945787
      supporting_text: "in the endoplasmic reticulum membrane, decarboxylates"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9945822
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing the NSDHL reaction converting
      4a-carboxy-4b-methyl-5a-cholest-8-en-3b-ol to 4a-methyl-5a-cholest-8-en-3b-ol to
      the ER membrane.
    action: ACCEPT
    reason: >-
      Correct ER-membrane localization for a specific NSDHL decarboxylation step.
    supported_by:
    - reference_id: Reactome:R-HSA-9945822
      supporting_text: "in the endoplasmic reticulum membrane, decarboxylates"
- term:
    id: GO:0003854
    label: 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity
  evidence_type: TAS
  original_reference_id: PMID:10710235
  qualifier: enables
  review:
    summary: >-
      Legacy (2003 PINC) TAS annotation using the classic steroidogenic
      3-beta-hydroxy-Delta5-steroid dehydrogenase activity (GO:0003854, the
      pregnenolone-to-progesterone-type reaction: a 3-beta-hydroxy-Delta(5)-steroid +
      NAD+ = a 3-oxo-Delta(5)-steroid + NADH). NSDHL belongs to the 3-beta-HSD family
      by fold, but its actual reaction is the NAD(P)+-dependent
      3-beta-hydroxysteroid-4alpha-carboxylate dehydrogenation and decarboxylation, not
      the Delta5-3-ketosteroid-isomerase-associated steroidogenic reaction. The cited
      abstract only states NSDHL is a 3beta-hydroxysteroid dehydrogenase functioning in
      the cholesterol biosynthetic pathway, not this specific steroidogenic activity.
    action: MODIFY
    reason: >-
      Family-level over-/mis-specific term: GO:0003854 denotes the steroidogenic
      Delta5-3-beta-HSD reaction that NSDHL does not catalyze. The essence (a
      3-beta-hydroxysteroid dehydrogenase in cholesterol biosynthesis) is sound, so
      replace with the accurate C4-decarboxylase term GO:0000252.
    proposed_replacement_terms:
    - id: GO:0000252
      label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
    supported_by:
    - reference_id: PMID:10710235
      supporting_text: "a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:10710235
  qualifier: involved_in
  review:
    summary: >-
      Legacy (2003 PINC) TAS annotation to cholesterol biosynthetic process, supported
      by the CHILD-syndrome report describing NSDHL as a 3-beta-hydroxysteroid
      dehydrogenase functioning in the cholesterol biosynthetic pathway.
    action: ACCEPT
    reason: >-
      Correct core biological process; duplicate of the Reactome-sourced cholesterol
      biosynthetic process annotations.
    supported_by:
    - reference_id: PMID:10710235
      supporting_text: "functioning in the cholesterol biosynthetic pathway"
core_functions:
- description: >-
    NAD(P)+-dependent sterol-4alpha-carboxylate 3-dehydrogenase (decarboxylating)
    that catalyzes the C4-demethylation step of post-squalene cholesterol
    biosynthesis, oxidizing the 3-beta-hydroxyl of a 4-alpha-carboxysterol and
    decarboxylating it to a 3-oxosteroid plus CO2, in the ER membrane.
  molecular_function:
    id: GO:0000252
    label: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/NSDHL/NSDHL-uniprot.txt
    supporting_text: "NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10369263
  title: The gene mutated in bare patches and striated mice encodes a novel 3beta-hydroxysteroid
    dehydrogenase.
  findings:
  - statement: >-
      Nsdhl encodes an NAD(P)H steroid dehydrogenase-like protein; sterol profiling of
      affected Bpa mice supports a role for Nsdhl in cholesterol biosynthesis, and this
      locus is the first mammalian X-linked dominant male-lethal locus.
    supporting_text: "Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Identifies the gene and establishes its role in cholesterol
      biosynthesis via mouse Bpa/Str alleles; abstract-only cache.
- id: PMID:10710235
  title: Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase,
    cause CHILD syndrome.
  findings:
  - statement: >-
      NSDHL encodes a 3-beta-hydroxysteroid dehydrogenase functioning in the cholesterol
      biosynthetic pathway; mutations cause CHILD syndrome (X-linked dominant, male-lethal).
    supporting_text: "encoding a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes NSDHL-CHILD syndrome link and cholesterol-pathway
      role; abstract-only cache.
- id: PMID:14741744
  title: Identification of major proteins in the lipid droplet-enriched fraction isolated
    from the human hepatocyte cell line HuH7.
  findings:
  - statement: >-
      Proteomic identification of lipid-droplet-associated proteins in human HuH7
      hepatocytes; used as IDA support for NSDHL lipid-droplet localization.
    supporting_text: "a fraction enriched with lipid droplets was isolated"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Lipid-droplet proteomics; the abstract does not name NSDHL specifically (curator
      full-text-based IDA), so treated as supporting the LD localization only.
- id: PMID:21129721
  title: Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome.
  findings:
  - statement: >-
      NSDHL encodes an enzyme in the cholesterol biosynthesis pathway; temperature-sensitive
      hypomorphic alleles cause CK syndrome, and the study characterized NSDHL subcellular
      (ER membrane) location.
    supporting_text: "encodes an enzyme in the cholesterol biosynthesis pathway"
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Basis for the EXP ER-membrane localization and CK syndrome
      association; abstract-only cache.
- id: PMID:21498505
  title: Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid
    droplets where they catalyze the formation of phosphatidylcholine.
  findings:
  - statement: >-
      Demonstrates that ER lipid enzymes additionally localize to lipid droplets; used
      as IDA support for NSDHL lipid-droplet association.
    supporting_text: "both enzymes additionally localize to lipid droplets"
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      About LPCAT1/2; the abstract does not mention NSDHL (curator full-text IDA).
      Supports the LD localization context.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      HuRI systematic yeast-two-hybrid binary interactome; source of a bare
      'protein binding' IPI for NSDHL (partner RHBDD1) that is uninformative about
      molecular function.
    supporting_text: "reference interactome map of human binary protein interactions, or 'HuRI'"
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome screen; correctly cited but yields only uninformative
      'protein binding'.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: >-
      Interactome-mapping study; source of a bare 'protein binding' IPI for NSDHL
      (partner ATXN1) that does not describe a specific molecular function.
    supporting_text: "Interactome maps are valuable resources to elucidate protein function"
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome screen; correctly cited but uninformative for MF.
- id: Reactome:R-HSA-194642
  title: 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol is decarboxylated and oxidized
    to form 4-methylcholesta-8(9),24-dien-3-one
  findings:
  - statement: >-
      NSDHL catalyzes this ER decarboxylation/oxidation step of cholesterol biosynthesis.
    supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- id: Reactome:R-HSA-194718
  title: 4-carboxycholesta-8(9),24-dien-3beta-ol is decarboxylated and oxidized to
    form cholesta-8(9),24-dien-3-one (zymosterone)
  findings:
  - statement: >-
      NSDHL catalyzes this ER decarboxylation/oxidation step producing zymosterone.
    supporting_text: "This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL"
- id: Reactome:R-HSA-6807047
  title: Cholesterol biosynthesis via desmosterol (Bloch pathway)
  findings: []
- id: Reactome:R-HSA-6807062
  title: Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)
  findings: []
- id: Reactome:R-HSA-9945787
  title: NSDHL decarboxylates 4a-carboxy-5a-cholest-8-ene-3b-ol to 5a-cholest-8-en-3-one
  findings:
  - statement: >-
      NSDHL, in the ER membrane, decarboxylates 4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol
      to 5alpha-cholest-8-en-3-one.
    supporting_text: "in the endoplasmic reticulum membrane, decarboxylates"
- id: Reactome:R-HSA-9945822
  title: NSDHL decarboxylates 4a-carboxy-4b-methyl-5a-cholest-8-en-3b-ol to 4a-methyl-5a-cholest-8-en-3b-ol
  findings:
  - statement: >-
      NSDHL, in the ER membrane, decarboxylates 4a-carboxy-4b-methyl-5a-cholest-8-en-3b-ol
      to 4a-methyl-5a-cholest-8-en-3b-ol.
    supporting_text: "in the endoplasmic reticulum membrane, decarboxylates"
- id: file:human/NSDHL/NSDHL-uniprot.txt
  title: UniProtKB entry Q15738 (NSDHL_HUMAN), Sterol-4-alpha-carboxylate 3-dehydrogenase,
    decarboxylating
  findings:
  - statement: >-
      UniProt describes NSDHL as catalyzing the NAD(P)+-dependent oxidative
      decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene
      cholesterol biosynthesis, localized to the ER membrane (single-pass) and lipid
      droplet.
    supporting_text: "Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis"