CERS1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that CERS1 acts in the endoplasmic reticulum. This is consistent with all experimental evidence for CerS enzymes acting at the ER membrane. Reason: CERS1 is an ER membrane enzyme; the ER localization is well supported experimentally (H183Q variant expressed and localized properly to the ER) and by UniProt. IBA at the organelle level is appropriate, though ER membrane (GO:0005789) is the more precise compartment. Supporting Evidence: PMID:24782409 CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.
GO:0046513 ceramide biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference that CERS1 is involved in ceramide biosynthesis. This is the core biological process for this gene and its orthologs across eukaryotes. Reason: Ceramide biosynthesis is the defining, experimentally established role of CERS1. IBA correctly captures the conserved family function. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of ceramide synthases (CerS), each of which displays a high specificity towards acyl CoAs of different chain lengths
GO:0050291 sphingosine N-acyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) inference of the ceramide-synthase molecular function (sphingosine/sphingoid-base N-acyltransferase). This is the core catalytic activity. Reason: The sphingoid-base N-acyltransferase (ceramide synthase) activity is the core molecular function of CERS1, established biochemically and conserved across the CerS/LAG1 family. Supporting Evidence: PMID:12869556 several human LAG1 homologues can rescue the viability of lag1delta lac1delta yeast cells and restore acyl-CoA-dependent ceramide and sphingolipid
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: Automated (ARBA/UniProt SubCell SL-0097) assignment to the ER membrane, the precise compartment where CERS1 resides as a multi-pass membrane protein. Reason: Correct and appropriately specific; matches the experimentally determined ER membrane localization in UniProt. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO (TLC domain, IPR006634) mapping to the generic term membrane. CERS1 is a multi-pass membrane protein, but this is far less informative than the ER membrane annotation also present. Reason: Not wrong, but membrane is uninformatively general given the more specific, experimentally supported endoplasmic reticulum membrane (GO:0005789) annotation. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt Multi-pass membrane protein
GO:0046513 ceramide biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Automated (ARBA + ortholog P27545) assignment to ceramide biosynthetic process, the core BP for CERS1. Reason: Redundant with the experimental and IBA ceramide biosynthetic process annotations and correct. Supporting Evidence: PMID:24782409 CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.
GO:0050291 sphingosine N-acyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated assignment (ARBA + ortholog P27545 + RHEA:23768/36691 + EC:2.3.1.24) of the core ceramide-synthase catalytic activity. Reason: Correct core molecular function; consistent with the RHEA/EC cross-references in UniProt and the experimental IDA annotations. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of ceramide synthases (CerS)
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl ortholog-based (mouse P27545) transfer of ER localization. Reason: Correct; CERS1 is an ER protein. Redundant with the experimental ER annotations. Supporting Evidence: PMID:12105227 UOG1 was localized to the endoplasmic reticulum
GO:0010614 negative regulation of cardiac muscle hypertrophy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl ortholog-projected phenotype (from rat A6KA58) linking CERS1/C18-ceramide to suppression of cardiac muscle hypertrophy. This is a downstream physiological/phenotypic consequence in a specific tissue, not the enzyme's core molecular role. Reason: Plausible tissue-specific downstream effect of altered ceramide levels, transferred from a rodent ortholog. Retain as non-core rather than remove, since it is an experimentally-anchored ortholog transfer; it does not represent the core sphingolipid biosynthetic function.
GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl ortholog-based (mouse P27545) transfer of the parent acyltransferase activity. This is a broad ancestor of the specific sphingosine N-acyltransferase activity (GO:0050291) already annotated. Reason: Correct but too general; the specific ceramide-synthase activity (GO:0050291) captures the same function more informatively. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of ceramide synthases (CerS)
GO:0046325 negative regulation of D-glucose import across plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl ortholog-projected (mouse P27545) role of CERS1/C18-ceramide in suppressing glucose uptake, consistent with UniProt's By-similarity description of a skeletal-muscle role in whole-body glucose metabolism. Downstream physiological effect, not core. Reason: Supported at the ortholog/By-similarity level as a metabolic consequence of C18-ceramide production; retain as a non-core downstream process rather than the core biosynthetic function. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt suppressing the uptake of glucose in multiple
GO:0030148 sphingolipid biosynthetic process	TAS Reactome:R-HSA-1660661	ACCEPT	Summary: Reactome (Sphingolipid de novo biosynthesis) traceable assignment of CERS1 to sphingolipid biosynthesis, the pathway parent of ceramide biosynthesis. Reason: Correct; CERS1 performs the N-acylation step within de novo sphingolipid biosynthesis. Supporting Evidence: PMID:12869556 several human LAG1 homologues can rescue the viability of lag1delta lac1delta yeast cells and restore acyl-CoA-dependent ceramide and sphingolipid
GO:0050291 sphingosine N-acyltransferase activity	IDA PMID:17977534 Kinetic characterization of mammalian ceramide synthases: de...	ACCEPT	Summary: Direct biochemical assay characterizing the kinetics of mammalian ceramide synthases, including CerS1, toward sphinganine, confirming the sphingoid-base N-acyltransferase (ceramide synthase) activity. Reason: Core molecular function directly measured; CerS1 N-acylates sphingoid bases using acyl-CoA. This is one of the defining experimental annotations. Supporting Evidence: PMID:17977534 K(m) values towards sphinganine
GO:0098554 cytoplasmic side of endoplasmic reticulum membrane	IDA PMID:24782409 Impairment of ceramide synthesis causes a novel progressive ...	ACCEPT	Summary: Assignment of CERS1 activity to the cytoplasmic (cytosolic) face of the ER membrane. Topology studies of the CerS/Lass family place the conserved Lag1 motif with the C-terminal (catalytic) region facing the cytosolic side of the ER membrane. Reason: Consistent with the ER membrane localization and with membrane-topology data for the family (C-terminus cytosolic). Retain as a refinement of the ER membrane annotation. Supporting Evidence: PMID:15823095 the C-terminus of Lass6 faces the cytosolic side of the membrane
GO:0006665 sphingolipid metabolic process	IEA GO_REF:0000041	ACCEPT	Summary: UniPathway (UPA00222) mapping to the broad sphingolipid metabolic process. Correct but general; CERS1 specifically performs a biosynthetic step. Reason: Correct parent process. The more specific sphingolipid/ceramide biosynthetic process annotations are also present; UniProt records the PATHWAY sphingolipid metabolism. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt Lipid metabolism; sphingolipid metabolism
GO:0050291 sphingosine N-acyltransferase activity	TAS Reactome:R-HSA-428185	ACCEPT	Summary: Reactome (Ceramide synthases transfer acyl-CoA onto sphingoid) traceable assignment of the core ceramide-synthase catalytic activity. Reason: Correct core molecular function, redundant with the experimental and IBA annotations. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of ceramide synthases (CerS)
GO:0005789 endoplasmic reticulum membrane	EXP PMID:24782409 Impairment of ceramide synthesis causes a novel progressive ...	ACCEPT	Summary: Experimental localization of CERS1 to the ER membrane (the EPM8-associated H183Q variant was shown to be expressed and localized properly to the ER). Reason: Core, experimentally supported subcellular localization at the correct compartment. Supporting Evidence: PMID:24782409 CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.
GO:0006686 sphingomyelin biosynthetic process	IDA PMID:29632068 Eleven residues determine the acyl chain specificity of cera...	KEEP AS NON CORE	Summary: Experimental annotation linking CERS1 to sphingomyelin biosynthesis. As the ceramide synthase producing C18-ceramide, CERS1 supplies the ceramide backbone that is downstream converted to sphingomyelin; the cited study dissected acyl-chain specificity determinants of the CerS family. Reason: CERS1 contributes the ceramide precursor for sphingomyelin, but sphingomyelin synthesis per se is a downstream pathway carried out by sphingomyelin synthases. This is an experimental (IDA) curator annotation whose full text I cannot fully verify from the cached abstract; per policy I defer to the curator and retain it as a non-core contributory process rather than removing it. Supporting Evidence: PMID:29632068 family of six ceramide synthases (CerS)
GO:0046513 ceramide biosynthetic process	IDA PMID:36170811 De novo sphingolipid biosynthesis necessitates detoxificatio...	ACCEPT	Summary: Experimental annotation placing CERS1 in ceramide biosynthesis in the context of a study of de novo sphingolipid biosynthesis and its detoxification requirement in cancer cells. Reason: Ceramide biosynthesis is the core process for CERS1. This is an experimental (IDA) annotation by the curator; although the cached full text foregrounds KDSR/SPT in the de novo pathway, the pathway measured includes ceramide species and CERS1 is a canonical de novo ceramide synthase, so I accept and defer to the curator per policy. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt N-acylates
GO:0046513 ceramide biosynthetic process	IDA PMID:22922758 Ceramide targets autophagosomes to mitochondria and induces ...	ACCEPT	Summary: Experimental demonstration that CerS1 expression generates endogenous C18-ceramide (and a catalytically dead H183A mutant does not), directly evidencing ceramide biosynthesis. Reason: Directly supports the core ceramide biosynthetic function: induction of wild-type CerS1 selectively increased C18-ceramide, while the His183Ala catalytic mutant did not. Supporting Evidence: PMID:22922758 C(18)-ceramide generation by ceramide synthase 1 (CerS1) expression mediates
GO:1901526 positive regulation of mitophagy	IDA PMID:22922758 Ceramide targets autophagosomes to mitochondria and induces ...	KEEP AS NON CORE	Summary: CerS1-generated C18-ceramide anchors LC3B-II autophagolysosomes to the mitochondrial outer membrane, driving lethal mitophagy; a catalytically inactive CerS1 mutant fails to do so. This is a signaling/effector consequence of C18-ceramide, downstream of the enzyme's biosynthetic role. Reason: Well-supported but represents a downstream, context-specific (tumor-suppressive mitophagy) signaling role of the C18-ceramide product rather than the core biosynthetic function of the enzyme. Supporting Evidence: PMID:22922758 CerS1/C18-ceramide was necessary and sufficient for induction of lethal mitophagy
GO:0005783 endoplasmic reticulum	IDA PMID:24782409 Impairment of ceramide synthesis causes a novel progressive ...	ACCEPT	Summary: Experimental ER localization of CERS1 (EPM8 study). Reason: Correct core localization; the ER membrane annotation from the same study is more precise. Supporting Evidence: PMID:24782409 CerS1, a transmembrane protein of the endoplasmic reticulum (ER)
GO:0046513 ceramide biosynthetic process	IDA PMID:24782409 Impairment of ceramide synthesis causes a novel progressive ...	ACCEPT	Summary: Experimental evidence that CERS1 catalyzes C18-ceramide biosynthesis; the EPM8 mutation decreases C18-ceramide levels. Reason: Core biological process, directly evidenced by loss of C18-ceramide with the pathogenic variant. Supporting Evidence: PMID:24782409 We demonstrated that the mutation decreases C18-ceramide levels.
GO:0050291 sphingosine N-acyltransferase activity	IDA PMID:24782409 Impairment of ceramide synthesis causes a novel progressive ...	ACCEPT	Summary: Experimental characterization of CERS1 as a ceramide synthase; the EPM8 H183Q variant shows impaired ceramide synthase activity. Reason: Core molecular function; the catalytic activity is directly implicated by the activity-impairing pathogenic variant. Supporting Evidence: PMID:24782409 CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides.
GO:0005783 endoplasmic reticulum	IDA PMID:17699106 (Dihydro)ceramide synthase 1 regulated sensitivity to cispla...	ACCEPT	Summary: CERS1 (LASS1) localizes to the ER under basal conditions; cisplatin induces a specific ER-to-Golgi translocation. Reason: Correct basal ER localization, consistent with all other evidence. Supporting Evidence: PMID:17699106 translocation of LASS1/CerS1, but not LASS4/CerS4 or
GO:0005783 endoplasmic reticulum	IDA PMID:19800881 Stress-induced ER to Golgi translocation of ceramide synthas...	ACCEPT	Summary: CerS1 resides in the ER under basal conditions and translocates to the Golgi upon diverse stresses (UV, DTT, chemotherapeutics). Reason: Correct basal ER localization. Supporting Evidence: PMID:19800881 CerS1 translocates from the endoplasmic reticulum
GO:0016020 membrane	TAS PMID:12869556 Human homologues of LAG1 reconstitute Acyl-CoA-dependent cer...	MARK AS OVER ANNOTATED	Summary: Traceable assignment of CERS1 to membrane (a broad term). CERS1 is a multi-pass ER membrane protein. Reason: Correct but uninformatively general relative to the ER membrane (GO:0005789) annotation. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt Multi-pass membrane protein
GO:0046513 ceramide biosynthetic process	IDA PMID:12869556 Human homologues of LAG1 reconstitute Acyl-CoA-dependent cer...	ACCEPT	Summary: Human LAG1 homologues (including CERS1) rescue yeast lacking acyl-CoA-dependent ceramide synthase and restore ceramide/sphingolipid biosynthesis. Reason: Core biological process, directly demonstrated by functional complementation in yeast. Supporting Evidence: PMID:12869556 restore acyl-CoA-dependent ceramide and sphingolipid
GO:0046513 ceramide biosynthetic process	IDA PMID:15823095 Mammalian Lass6 and its related family members regulate synt...	ACCEPT	Summary: Overexpression of Lass1 (CERS1) preferentially increases C18:0-ceramide, demonstrating its role in ceramide biosynthesis with C18 acyl-chain specificity. Reason: Core biological process, directly evidenced by the ceramide species produced upon overexpression. Supporting Evidence: PMID:15823095 increased C18:0-ceramide levels preferentially
GO:0046513 ceramide biosynthetic process	IDA PMID:18541923 2-Hydroxy-ceramide synthesis by ceramide synthase family: en...	ACCEPT	Summary: In vitro CerS assays confirmed CerS1 can also utilize 2-hydroxy-stearoyl-CoA, producing 2-hydroxy-C18-ceramide, extending its ceramide biosynthetic role to 2-hydroxy species. Reason: Supports ceramide biosynthesis (including 2-hydroxy-ceramide) with retained C18 chain-length specificity; consistent with the core biosynthetic function. Supporting Evidence: PMID:18541923 CerS1 to utilize 2-hydroxy-stearoyl-CoA as a substrate
GO:0071466 cellular response to xenobiotic stimulus	IDA PMID:19800881 Stress-induced ER to Golgi translocation of ceramide synthas...	KEEP AS NON CORE	Summary: Diverse stresses, including drugs/xenobiotics, trigger a specific proteasome-dependent ER-to-Golgi translocation of CerS1. This is a stress-response behavior of the protein, not its core biosynthetic function. Reason: Experimentally supported response of CERS1 to xenobiotic/drug stress via regulated translocation, but a peripheral regulatory behavior rather than the core function. Supporting Evidence: PMID:19800881 wide variety of stresses result in the specific translocation of CerS1
GO:0071492 cellular response to UV-A	IDA PMID:19800881 Stress-induced ER to Golgi translocation of ceramide synthas...	KEEP AS NON CORE	Summary: UV light induces the specific ER-to-Golgi translocation and proteolytic processing of CerS1, evidencing a UV stress response. Reason: Real, experimentally supported stress-response behavior, but peripheral to the core ceramide-biosynthetic role. Supporting Evidence: PMID:19800881 UV-light (which causes pyrimidine dimer formation) or DTT
GO:0072721 cellular response to dithiothreitol	IDA PMID:19800881 Stress-induced ER to Golgi translocation of ceramide synthas...	KEEP AS NON CORE	Summary: DTT (an ER-stress/UPR inducer) triggers the specific CerS1 ER-to-Golgi translocation. Reason: Experimentally supported stress response, but peripheral to the core biosynthetic function. Supporting Evidence: PMID:19800881 UV-light (which causes pyrimidine dimer formation) or DTT
GO:0030148 sphingolipid biosynthetic process	IDA PMID:12105227 Upstream of growth and differentiation factor 1 (uog1), a ma...	ACCEPT	Summary: UOG1 (CERS1) expression regulates C18-(dihydro)ceramide synthesis and channels product into neutral glycosphingolipids, evidencing a role in sphingolipid biosynthesis. Reason: Core biological process (sphingolipid/ceramide biosynthesis), directly demonstrated by the increase in C18 sphingolipids and elevated CerS activity with stearoyl-CoA. Supporting Evidence: PMID:12105227 impacts neutral glycosphingolipid synthesis
GO:0046513 ceramide biosynthetic process	IDA PMID:12105227 Upstream of growth and differentiation factor 1 (uog1), a ma...	ACCEPT	Summary: UOG1 (CERS1) expression regulates synthesis of C18-(dihydro)ceramide (N-stearoyl- sphinganine), directly evidencing its role in ceramide biosynthesis with C18 specificity. Reason: Core biological process; the same study directly shows elevated ceramide synthase activity with stearoyl-CoA and increased C18-ceramide upon UOG1 expression. Supporting Evidence: PMID:12105227 regulates N-stearoyl-sphinganine
GO:0036146 cellular response to mycotoxin	IDA PMID:12105227 Upstream of growth and differentiation factor 1 (uog1), a ma...	KEEP AS NON CORE	Summary: UOG1 (CERS1) confers fumonisin B1 (a mycotoxin) resistance for cellular ceramide production, evidencing a cellular response to the mycotoxin. Reason: Experimentally supported response to the mycotoxin fumonisin B1, but a peripheral phenotype linked to CERS1 activity rather than its core biosynthetic function. Supporting Evidence: PMID:12105227 fumonisin B(1) resistance with respect to the ability of the cells to continue
GO:0046513 ceramide biosynthetic process	IDA PMID:17548428 Mechanisms of ceramide-mediated repression of the human telo...	ACCEPT	Summary: Generation of C18-ceramide via CerS1 expression (but not C16-ceramide via CerS5/CerS6) represses the hTERT promoter, evidencing CERS1-dependent C18-ceramide biosynthesis. Reason: Supports the core ceramide biosynthetic function (specific production of C18-ceramide by CerS1). The hTERT repression itself is a downstream signaling consequence. Supporting Evidence: PMID:17548428 generation of C18-ceramide via
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-428185	ACCEPT	Summary: Reactome (Ceramide synthases transfer acyl-CoA onto sphingoid) traceable assignment of CERS1 to the ER membrane. Reason: Correct and appropriately specific compartment. Supporting Evidence: file:human/CERS1/CERS1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0046513 ceramide biosynthetic process	ISS GO_REF:0000024	ACCEPT	Summary: Curator sequence-similarity transfer from mouse ortholog P27545 for the core ceramide biosynthetic process. Reason: Correct core process, redundant with abundant experimental support. Supporting Evidence: PMID:15823095 increased C18:0-ceramide levels preferentially
GO:0050291 sphingosine N-acyltransferase activity	ISS GO_REF:0000024	ACCEPT	Summary: Curator sequence-similarity transfer from mouse ortholog P27545 for the core ceramide-synthase catalytic activity. Reason: Correct core molecular function, redundant with experimental IDA support. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base by a family of ceramide synthases (CerS)

Gene Description

Existing Annotations Review

Core Functions

Sphingoid-base N-acyltransferase (ceramide synthase) that N-acylates sphinganine (and sphingosine in the salvage pathway) using acyl-CoA, with high selectivity for stearoyl-CoA (C18:0-CoA), to produce C18-(dihydro)ceramide in de novo sphingolipid biosynthesis.

References

Suggested Questions for Experts

Suggested Experiments

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Notes

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