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).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Accurate but general; the specific activity is captured by GO:0000252. Retained as a correct (non-core) grouping term. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt NAD(P)(+)-dependent oxidative decarboxylation |
| GO:0008203 cholesterol metabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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). Supporting Evidence: PMID:10369263 Quantitative analysis of sterols from tissues of affected Bpa mice support a role for Nsdhl in cholesterol biosynthesis |
| GO:0000252 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt a 3beta-hydroxysteroid-4alpha-carboxylate + NADP(+) = a 3- oxosteroid + CO2 + NADPH |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | 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). Reason: Correct and experimentally corroborated (EXP, IC). Represents the precise site of the enzyme in the ER-membrane C4-demethylation complex. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005811 lipid droplet | IEA GO_REF:0000120 | ACCEPT | 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). 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. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Lipid droplet |
| GO:0006694 steroid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | 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. Reason: Accurate parent process. Retained as a valid (non-core) grouping term; the specific process is cholesterol biosynthetic process (GO:0006695). Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt C4 methyl groups of 4-alpha-carboxysterols in post-squalene |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000002 | ACCEPT | 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. Reason: Accurate parent MF term consistent with the NAD(P)+-dependent CH-OH dehydrogenation NSDHL performs. Retained as a correct (non-core) grouping term. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt NAD(P)(+)-dependent oxidative decarboxylation |
| GO:0102175 3-beta-hydroxysteroid dehydrogenase (NAD+)/C4-decarboxylase activity | IEA GO_REF:0000116 | ACCEPT | 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. Reason: Correct, specific molecular function reflecting the NAD+ cofactor variant of EC 1.1.1.170. Supported additionally by ISS from the mouse ortholog. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3- oxosteroid + CO2 + NADH |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | 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. 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). Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions, or 'HuRI' |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara orthology transfer (from mouse Q9R1J0) of endoplasmic reticulum localization. Consistent with all experimental and phylogenetic evidence for ER localization of NSDHL. Reason: Correct compartment, corroborated by IDA and IBA annotations to the same term. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-6807047 | ACCEPT | 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. Reason: This is the precise core biological process for NSDHL. Both the Bloch and Kandutsch-Russell routes share the NSDHL-catalyzed C4-demethylation steps. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt post-squalene cholesterol biosynthesis |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-6807062 | ACCEPT | 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. Reason: Correct core biological process, identical to the Bloch-pathway annotation; the two Reactome pathway objects reflect the branched post-zymosterol routes. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt post-squalene cholesterol biosynthesis |
| GO:0000252 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity | EXP PMID:10369263 The gene mutated in bare patches and striated mice encodes a... | ACCEPT | 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. Reason: Core molecular function with experimental support in the mammalian ortholog; duplicate GO term (with IEA/ISS/TAS) is expected and appropriate. Supporting Evidence: PMID:10369263 encoding an NAD(P)H steroid dehydrogenase-like protein |
| GO:0000252 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity | TAS Reactome:R-HSA-194642 | ACCEPT | 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. Reason: Correct, specific representation of NSDHL's core catalytic activity within a defined cholesterol-biosynthesis reaction. Supporting Evidence: Reactome:R-HSA-194642 This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL |
| GO:0000252 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity | TAS Reactome:R-HSA-194718 | ACCEPT | 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. Reason: Correct, specific representation of NSDHL's core activity in another cholesterol-biosynthesis C4-decarboxylation step. Supporting Evidence: Reactome:R-HSA-194718 This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct assay (immunofluorescence, Human Protein Atlas) localizing NSDHL to the endoplasmic reticulum. Consistent with the enzyme's established ER-membrane residence. Reason: Experimental (IDA) support for the correct compartment. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005811 lipid droplet | IDA GO_REF:0000052 | ACCEPT | 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. Reason: Experimental support for a genuine secondary localization; non-core relative to the ER site of catalysis. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Lipid droplet |
| GO:0005789 endoplasmic reticulum membrane | IC PMID:10710235 Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid... | ACCEPT | 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. Reason: Correct site-of-action for this membrane-embedded sterol enzyme; consistent with the EXP localization (PMID:21129721) and UniProt. Supporting Evidence: PMID:10710235 a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway |
| GO:0000252 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Well-justified orthology-based assignment of NSDHL's defining molecular function. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt EC=1.1.1.170 {ECO:0000250|UniProtKB:Q9R1J0} |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:21129721 Hypomorphic temperature-sensitive alleles of NSDHL cause CK ... | ACCEPT | 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. Reason: Direct experimental support (EXP) for the enzyme's site in the ER membrane. Supporting Evidence: PMID:21129721 encodes an enzyme in the cholesterol biosynthesis pathway |
| GO:0005811 lipid droplet | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of lipid-droplet localization from the mouse ortholog (UniProtKB:Q9R1J0). Corroborated by human IDA lipid-droplet evidence. Reason: Consistent with experimental lipid-droplet localization in human cells; a valid non-core localization. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Lipid droplet {ECO:0000250|UniProtKB:Q9R1J0} |
| GO:0102175 3-beta-hydroxysteroid dehydrogenase (NAD+)/C4-decarboxylase activity | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Correct, specific NAD+ variant of NSDHL's core molecular function; orthology support is appropriate. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3- oxosteroid + CO2 + NADH |
| GO:0005811 lipid droplet | IDA PMID:21498505 Human lysophosphatidylcholine acyltransferases 1 and 2 are l... | ACCEPT | 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. Reason: Direct-assay support for a genuine secondary localization; non-core relative to catalysis in the ER membrane. Supporting Evidence: PMID:21498505 both enzymes additionally localize to lipid droplets |
| GO:0005811 lipid droplet | IDA PMID:14741744 Identification of major proteins in the lipid droplet-enrich... | ACCEPT | 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. Reason: Direct-assay (proteomic) support for the lipid-droplet localization; consistent with other IDA/ISS evidence. Non-core. Supporting Evidence: PMID:14741744 a fraction enriched with lipid droplets was isolated |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | ACCEPT | Summary: Direct localization (LIFEdb, GFP-fusion in living cells) of NSDHL to the endoplasmic reticulum. Consistent with all other ER evidence. Reason: Experimental support for the correct compartment. Supporting Evidence: file:human/NSDHL/NSDHL-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-194642 | ACCEPT | Summary: Reactome TAS localizing the NSDHL-catalyzed decarboxylation reaction to the ER membrane. Consistent with EXP/IC/IDA evidence for ER-membrane residence. Reason: Correct localization to the site of the C4-demethylation complex. Supporting Evidence: Reactome:R-HSA-194642 This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-194718 | ACCEPT | Summary: Reactome TAS localizing another NSDHL decarboxylation reaction (to zymosterone) to the ER membrane. Duplicate of the correct ER-membrane localization. Reason: Correct localization; duplicate ER-membrane TAS from a related Reactome reaction. Supporting Evidence: Reactome:R-HSA-194718 This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9945787 | ACCEPT | 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. Reason: Correct ER-membrane localization for a specific NSDHL decarboxylation step. Supporting Evidence: Reactome:R-HSA-9945787 in the endoplasmic reticulum membrane, decarboxylates |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9945822 | ACCEPT | 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. Reason: Correct ER-membrane localization for a specific NSDHL decarboxylation step. Supporting Evidence: Reactome:R-HSA-9945822 in the endoplasmic reticulum membrane, decarboxylates |
| GO:0003854 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity | TAS PMID:10710235 Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid... | MODIFY | 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. 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 replacements: 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity Supporting Evidence: PMID:10710235 a 3beta-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway |
| GO:0006695 cholesterol biosynthetic process | TAS PMID:10710235 Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid... | ACCEPT | 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. Reason: Correct core biological process; duplicate of the Reactome-sourced cholesterol biosynthetic process annotations. Supporting Evidence: PMID:10710235 functioning in the cholesterol biosynthetic pathway |
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