CERS2 (ceramide synthase 2; formerly LASS2/LAG1 longevity assurance homolog 2) is a multi-pass endoplasmic reticulum membrane enzyme of the sphingosine N-acyltransferase (Lag1/Lac1, TLC-domain) family. It catalyzes the N-acylation step of ceramide biosynthesis, transferring a fatty acyl chain from acyl-CoA onto the amino group of a sphingoid base (sphinganine in the de novo pathway, sphingosine in the salvage pathway) to form (dihydro)ceramide. Its defining feature is high selectivity for very-long-chain (VLC) acyl-CoAs (C22-C24, up to C26), so it produces very-long-chain ceramides. CERS2 is the most highly and most broadly expressed of the six mammalian ceramide synthases, with prominent expression in liver, kidney and brain, and its very-long-chain ceramides are important precursors for the myelin sphingolipids galactosylceramide and sulfatide. Acyl-chain selectivity is conferred by a short loop within the TLC (TRAM-LAG1-CLN8) domain, and the enzyme is regulated by C-terminal phosphorylation and by inhibition from sphingosine 1-phosphate.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that CERS2 is active in the endoplasmic reticulum. This is well supported: CERS2 is an ER-resident, multi-pass membrane ceramide synthase, and the ER is the site of de novo ceramide synthesis. Reason: Consistent with experimental localization of CERS2 to the ER membrane and with the ER being the site of de novo ceramide biosynthesis. The more specific ER membrane term (GO:0005789) is captured in the core functions. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0046513 ceramide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that CERS2 is involved in ceramide biosynthesis. This is the core biological process of the gene. Reason: CERS2 catalyzes the N-acylation step of ceramide biosynthesis, producing very-long-chain (dihydro)ceramides. Strongly supported by direct enzymatic characterization and consistent across the CerS family phylogeny. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base PMID:18165233 rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis. |
| GO:0050291 sphingosine N-acyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of sphingosine N-acyltransferase (ceramide synthase) activity. This is the core molecular function of CERS2. Reason: This is the exact GO term GO uses for ceramide synthase activity and it is directly supported by biochemical assays of human CERS2 as well as being consistent across the CerS family. Retained as a core function. Supporting Evidence: PMID:17977534 each of which displays a high PMID:18165233 has the broadest tissue distribution. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | REMOVE | Summary: Electronic (InterPro2GO) annotation of DNA binding, transferred from the homeodomain-like signature (IPR001356) matching the CERS2 N-terminal Homeobox-like region. CERS2 does not bind DNA. Reason: This is a spurious InterPro homeodomain-signature transfer. UniProt states explicitly that the predicted Homeobox domain lacks residues needed for DNA binding and, given ER-membrane localization, does not constitute a canonical homeobox domain. CERS2 is an ER-membrane ceramide synthase with no DNA-binding role, so this IEA mapping is incorrect. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt The predicted Homeobox domain (Homeobox-like region) lacks |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/UniProt SubCell) annotation of ER membrane localization. This is the correct, specific compartment for CERS2. Reason: Matches the experimentally determined subcellular location; CERS2 is a multi-pass ER membrane protein. Retained as a core cellular-component function. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from InterPro (TLC-domain signature). Reason: Not incorrect but uninformatively general. The specific ER membrane localization (GO:0005789) is well established and is the appropriate term, making the bare "membrane" annotation an over-annotation. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt Multi-pass membrane protein |
| GO:0046513 ceramide biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/orthology) annotation to ceramide biosynthetic process, the core BP of CERS2. Reason: Duplicates the well-supported core biological process; CERS2 catalyzes the N-acylation step of ceramide biosynthesis. Supporting Evidence: PMID:18165233 rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis. |
| GO:0050291 sphingosine N-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/RHEA/EC 2.3.1.24) annotation of sphingosine N-acyltransferase (ceramide synthase) activity, the core MF of CERS2. Reason: Duplicates the experimentally supported core molecular function. The RHEA and EC cross-references correspond to the ceramide synthase reaction that CERS2 catalyzes. Supporting Evidence: PMID:18165233 has the broadest tissue distribution. |
| GO:0005515 protein binding | IPI PMID:11543633 Cloning, mapping, and characterization of a human homologue ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the LASS2 cloning study, which reported yeast two-hybrid and GST pull-down interactions with membrane-associated receptors/transporters (ATP6V0C, ASGR1, ASGR2, SLC22A1/OCT1). Reason: "Protein binding" is an uninformative molecular-function term that does not capture CERS2's catalytic role. The underlying interactions are real but the bare term should not be treated as a core function. Per curation policy the experimental IPI is retained (not removed). Supporting Evidence: PMID:11543633 glutathione S-transferase pull-down assays showed that the LASS2 protein |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a large-scale mRNA-display interacting- region resource for human transcription factors. Reason: Bare, uninformative "protein binding" from a high-throughput interaction screen; does not describe CERS2's function. Retained (not removed) as an experimental IPI per policy but marked as over-annotated. Supporting Evidence: PMID:20195357 large-scale IR data set obtained using mRNA display |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a yeast-two-hybrid human liver protein interaction network. Reason: Uninformative "protein binding" from a proteome-scale Y2H map; does not inform CERS2 molecular function. Retained as an experimental IPI per policy. Supporting Evidence: PMID:21988832 human liver protein interaction network (HLPN) |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the HuRI reference binary interactome. Reason: Uninformative "protein binding" from a systematic binary interactome map. Does not describe CERS2 function; retained as experimental IPI per policy. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:32911434 A functionally defined high-density NRF2 interactome reveals... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from a high-density NRF2 (NFE2L2) interactome screen. Reason: Uninformative "protein binding" from a targeted NRF2 interactome; does not capture CERS2 molecular function. Retained as experimental IPI per policy. Supporting Evidence: PMID:32911434 high-density human NRF2 interactome |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the BioPlex 3.0 affinity-purification mass-spectrometry interactome. Reason: Uninformative "protein binding" from a proteome-scale AP-MS network; does not describe CERS2 function. Retained as experimental IPI per policy. Supporting Evidence: PMID:33961781 affinity-purification mass spectrometry |
| GO:0010626 negative regulation of Schwann cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively regulating Schwann cell proliferation. Reason: A plausible downstream/tissue-specific consequence of altering very-long-chain sphingolipid (myelin) composition, transferred from rat orthology. It is peripheral to the core enzymatic function and should be kept as a non-core annotation. |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000107 | MODIFY | Summary: Orthology-transferred (from mouse Q924Z4) general acyltransferase activity. Reason: Correct in essence (CERS2 transfers an acyl group) but too general; the specific ceramide-synthase activity term GO:0050291 (sphingosine N-acyltransferase activity) is the appropriate molecular function. Proposed replacements: sphingosine N-acyltransferase activity |
| GO:0019216 regulation of lipid metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred (from mouse Q924Z4) role in regulation of lipid metabolic process. Reason: Broad regulatory term. CERS2 shapes cellular sphingolipid (ceramide) composition, so it does influence lipid metabolism, but this general term is not the core molecular/biological function and is better kept as non-core. |
| GO:0048681 negative regulation of axon regeneration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively regulating axon regeneration. Reason: A peripheral, nervous-system-specific developmental role transferred from rat orthology, downstream of CERS2's effect on myelin sphingolipids. Kept as non-core. |
| GO:1900148 negative regulation of Schwann cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred (Ensembl Compara, from rat Q3T1K1) role in negatively regulating Schwann cell migration. Reason: Peripheral nervous-system-specific role transferred from rat orthology, downstream of altered sphingolipid composition. Kept as non-core. |
| GO:0030148 sphingolipid biosynthetic process | TAS Reactome:R-HSA-1660661 | KEEP AS NON CORE | Summary: Reactome (TAS) annotation placing CERS2 in sphingolipid de novo biosynthesis, the pathway superset of ceramide biosynthesis. Reason: Correct but more general than the specific ceramide biosynthetic process that CERS2 directly catalyzes. Kept as a valid but non-core (parent) BP annotation. Supporting Evidence: PMID:20937905 ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-based (IEA) annotation to the general sphingolipid metabolic process. Reason: A high-level parent of the specific ceramide biosynthetic process. Correct but too general to be a core function; kept as non-core. |
| GO:0050291 sphingosine N-acyltransferase activity | TAS Reactome:R-HSA-428185 | ACCEPT | Summary: Reactome (TAS) annotation of sphingosine N-acyltransferase (ceramide synthase) activity, the core MF. Reason: Correct core molecular function, consistent with biochemical characterization of CERS2. Supporting Evidence: PMID:18165233 has the broadest tissue distribution. |
| GO:0010626 negative regulation of Schwann cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer (from rat Q3T1K1) of negative regulation of Schwann cell proliferation. Reason: Duplicates the orthology-based Schwann-cell role; peripheral, nervous-system-specific and non-core. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (HPA immunofluorescence) localization to the endoplasmic reticulum. Reason: Consistent with the established ER-membrane localization of CERS2. The more specific ER membrane term is captured in core functions. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Direct (HPA immunofluorescence) annotation to the nuclear membrane. Reason: The nuclear membrane (outer nuclear envelope) is continuous with the ER, so a fraction of an ER-membrane enzyme can appear at the nuclear membrane. This is a minor/secondary localization, not the core ER-membrane site of activity; kept as non-core. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:18165233 Characterization of ceramide synthase 2: tissue distribution... | ACCEPT | Summary: Experimental localization of CERS2 to the ER membrane, the core cellular component for its activity. Reason: Directly supported experimental ER-membrane localization; this is the core compartment where CERS2 catalyzes ceramide synthesis. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0050291 sphingosine N-acyltransferase activity | EXP PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol... | ACCEPT | Summary: Experimental annotation of ceramide synthase activity in the study linking ELOVL1-derived C24 acyl-CoAs to CERS2-dependent C24 sphingolipid synthesis. Reason: CERS2 is characterized as the ceramide synthase essential for C24 (very-long-chain) sphingolipid synthesis, directly supporting its sphingosine N-acyltransferase activity. Core molecular function. Supporting Evidence: PMID:20937905 ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. |
| GO:0050291 sphingosine N-acyltransferase activity | IDA PMID:18165233 Characterization of ceramide synthase 2: tissue distribution... | ACCEPT | Summary: Direct assay of CERS2 ceramide synthase activity with defined VLC acyl-CoA specificity. Reason: Direct biochemical demonstration of sphingosine N-acyltransferase (ceramide synthase) activity for CERS2, with characteristic very-long-chain acyl-CoA specificity. Core molecular function. Supporting Evidence: PMID:18165233 rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis. |
| GO:0006688 glycosphingolipid biosynthetic process | EXP PMID:34080016 Glucosylceramide and galactosylceramide, small glycosphingol... | MARK AS OVER ANNOTATED | Summary: Annotation to glycosphingolipid biosynthetic process, citing a general review of glucosylceramide and galactosylceramide. Reason: CERS2 synthesizes the very-long-chain ceramide backbone that is a precursor for glycosphingolipids such as galactosylceramide/sulfatide, but it does not itself catalyze the glycosylation step of glycosphingolipid biosynthesis. The cited reference is a general GlcCer/GalCer review that does not establish a direct CERS2 role in glycosphingolipid biosynthesis, so annotating CERS2 to this specific process is an over-annotation. Its role is upstream (ceramide biosynthesis). Supporting Evidence: PMID:34080016 The galactosylceramides are enriched in very-long-chain |
| GO:0046513 ceramide biosynthetic process | IDA PMID:36170811 De novo sphingolipid biosynthesis necessitates detoxificatio... | ACCEPT | Summary: IDA annotation (UOS_MCB) to ceramide biosynthetic process citing a cancer de novo sphingolipid biosynthesis study. Reason: Ceramide biosynthesis is unquestionably the correct process for CERS2 and is independently and strongly supported by other experimental annotations to this same term. The cited paper (Spears et al.) is a de novo sphingolipid biosynthesis study; its cached text foregrounds the upstream SPT/KDSR enzymes and does not mention CERS2, but per curation policy the experimental IDA is not overruled from incomplete cached evidence when the function is clearly correct. Accepted, deferring to the curator; see reference_review note on the unverifiable citation. |
| GO:0098554 cytoplasmic side of endoplasmic reticulum membrane | IDA PMID:36170811 De novo sphingolipid biosynthesis necessitates detoxificatio... | UNDECIDED | Summary: IDA annotation (UOS_MCB) placing CERS2 activity on the cytoplasmic side of the ER membrane, citing the same cancer de novo sphingolipid study. Reason: A cytosolic-facing active site is topologically consistent with the CERS2 C-terminus being cytoplasmic (UniProt topology; C-terminal cytoplasmic phosphorylation), but the cited reference does not mention CERS2 in the cached full text and therefore cannot be verified as the source of this specific membrane-sidedness claim. Marked UNDECIDED rather than removed. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt TOPO_DOM 325..380 |
| GO:0019216 regulation of lipid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer (from mouse Q924Z4) of regulation of lipid metabolic process. Reason: Broad regulatory term duplicating the Ensembl IEA. CERS2 influences cellular ceramide/sphingolipid composition but this general term is non-core. |
| GO:0005783 endoplasmic reticulum | IDA PMID:18165233 Characterization of ceramide synthase 2: tissue distribution... | ACCEPT | Summary: Direct experimental localization of CERS2 to the endoplasmic reticulum. Reason: Consistent with the established ER-membrane localization of CERS2; the more specific ER membrane term is a core function. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0046513 ceramide biosynthetic process | IDA PMID:17977534 Kinetic characterization of mammalian ceramide synthases: de... | ACCEPT | Summary: Direct kinetic characterization of mammalian ceramide synthases including CERS2, supporting its role in ceramide biosynthesis. Reason: CERS2 is directly assayed as a ceramide synthase acting by N-acylation of a sphingoid base; core biological process. Supporting Evidence: PMID:17977534 ceramide is synthesized by N-acylation of a sphingoid long-chain base |
| GO:0046513 ceramide biosynthetic process | IDA PMID:18165233 Characterization of ceramide synthase 2: tissue distribution... | ACCEPT | Summary: Direct characterization of CERS2 ceramide-synthesizing activity with VLC acyl-CoA specificity. Reason: Directly supported core biological process; CERS2 makes very-long-chain ceramides. Supporting Evidence: PMID:18165233 rather utilizing longer acyl-chain CoAs (C20-C26) for ceramide synthesis. |
| GO:0046513 ceramide biosynthetic process | IDA PMID:29632068 Eleven residues determine the acyl chain specificity of cera... | ACCEPT | Summary: Direct study mapping the acyl-chain specificity of ceramide synthases, showing CERS2 generates C22-C24 ceramides. Reason: Directly demonstrates CERS2 ceramide-biosynthetic activity and its very-long-chain product specificity; core biological process. Supporting Evidence: PMID:29632068 containing 11 residues from CerS2 (which generates |
| GO:0050291 sphingosine N-acyltransferase activity | IDA PMID:17977534 Kinetic characterization of mammalian ceramide synthases: de... | ACCEPT | Summary: Direct kinetic assay of CERS2 sphingosine N-acyltransferase (ceramide synthase) activity. Reason: Direct biochemical support for the core molecular function. Supporting Evidence: PMID:17977534 each of which displays a high |
| GO:0050291 sphingosine N-acyltransferase activity | IDA PMID:29632068 Eleven residues determine the acyl chain specificity of cera... | ACCEPT | Summary: Direct demonstration of CERS2 ceramide synthase activity and its C22-C24 acyl-chain specificity. Reason: Direct experimental support for the core molecular function, with the very-long-chain acyl-CoA specificity that distinguishes CERS2. Supporting Evidence: PMID:29632068 containing 11 residues from CerS2 (which generates |
| GO:0048681 negative regulation of axon regeneration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer (from rat Q3T1K1) of negative regulation of axon regeneration. Reason: Duplicates the Ensembl IEA; peripheral nervous-system role, non-core. |
| GO:1900148 negative regulation of Schwann cell migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator ISS transfer (from rat Q3T1K1) of negative regulation of Schwann cell migration. Reason: Duplicates the Ensembl IEA; peripheral nervous-system role, non-core. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput proteomic detection of CERS2 in an NK-cell membrane proteome. Reason: Generic membrane localization from a high-throughput membrane-proteome study; uninformative relative to the specific ER-membrane localization. Over-annotation. Supporting Evidence: PMID:19946888 define the composition of the membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-428185 | ACCEPT | Summary: Reactome (TAS) annotation of ER membrane localization. Reason: Matches the experimentally established ER-membrane localization; core cellular component. Supporting Evidence: file:human/CERS2/CERS2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the study showing CERS2 interacts with the fatty-acid elongation machinery (ELOVL1, HSD17B12, TECR), coordinating C24 acyl-CoA production with its use for ceramide synthesis. Reason: This interaction is functionally meaningful (physical coupling of CERS2 to the VLC fatty-acid elongase complex), but the bare "protein binding" term is uninformative and does not represent a core molecular function. Retained (not removed) as an experimental IPI; the functional relationship is captured in the description and core functions. Supporting Evidence: PMID:20937905 ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. |
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