ACER1 (alkaline ceramidase 1; also acylsphingosine deacylase 3 / N-acylsphingosine amidohydrolase 3, ASAH3) is an integral, multi-pass endoplasmic-reticulum membrane enzyme that hydrolyses ceramide to sphingosine and a free fatty acid at alkaline pH (EC 3.5.1.23). It preferentially cleaves very-long-chain and unsaturated ceramides (e.g. C24:1- and C24:0-ceramide) with the natural D-erythro-sphingosine backbone, and can also hydrolyse dihydroceramides to dihydrosphingosine. Catalysis depends on a catalytic zinc ion and is influenced by calcium. ACER1 is one of three human alkaline ceramidases (ACER1/2/3) and is distinct from the acid (ASAH1) and neutral (ASAH2) ceramidases; unlike its paralogs it is expressed almost exclusively in skin/epidermis. By controlling the local ceramide-sphingosine-sphingosine-1-phosphate balance, ACER1 is a key regulator of keratinocyte proliferation and differentiation and contributes to epidermal permeability-barrier homeostasis. It sits in the sphingolipid catabolic pathway, generating the sphingosine that can be phosphorylated to the bioactive signalling lipid sphingosine-1-phosphate.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) localization to the endoplasmic reticulum. Correct but less precise than the experimentally supported ER membrane term; kept as non-core supporting localization (the specific location is captured by GO:0005789). Reason: ER localization is correct and consistent with the IDA/EXP evidence (PMID:17713573), but ACER1 is an integral ER membrane protein, so the membrane term is the precise core location. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ceramidase (N-acylsphingosine amidohydrolase; EC 3.5.1.23) activity is the core molecular function of ACER1, supported by direct experimental assays and the phylogenetic inference. This is the single ceramidase MF term in GO. Reason: Core catalytic function; corroborated by IDA/IMP annotations (PMID:17713573, PMID:20207939, PMID:20628055) and UniProt EC 3.5.1.23. |
| GO:0046512 sphingosine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: ACER1 generates sphingosine as the direct product of ceramide hydrolysis; a core biological process for this enzyme, also supported by direct experimental evidence. Reason: Direct product of the ceramidase reaction; corroborated by IDA/IMP annotations. |
| GO:0046514 ceramide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Breakdown of ceramide is the direct substrate side of the ceramidase reaction; a core biological process for ACER1. Reason: Direct consequence of the ceramidase activity; corroborated by IMP/ISS annotations. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Integral ER membrane localization, mapped electronically from the UniProt subcellular-location vocabulary. This is the precise core location and is independently supported by experimental evidence (EXP, PMID:17713573). Reason: Multi-pass ER membrane protein per UniProt; matches the EXP annotation. |
| GO:0006672 ceramide metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IPR008901, ACER family) mapping to ceramide metabolism. Correct but a broad parent of the more specific, experimentally supported ceramide catabolic process; kept as non-core. Reason: General parent term; the specific catabolic direction (GO:0046514) is the core BP. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Uninformative high-level membrane term from InterPro. The specific and correct location is the ER membrane (GO:0005789). Reason: Too general to be informative; superseded by the specific ER membrane annotation. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (multi-method, EC 3.5.1.23 / RHEA-based) assertion of the core ceramidase activity. Correct and consistent with the experimental IDA annotations. Reason: Redundant electronic support for the experimentally established core MF. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein-binding IPI from the HuRI proteome-scale yeast two-hybrid interactome (ACER1-MPP1). Uninformative about molecular function and with no established biological relevance for ACER1; over-annotated rather than core. Reason: High-throughput screen-only interaction; bare protein binding gives no functional information. Per policy, an IPI is not removed but is flagged as over-annotation. |
| GO:0046512 sphingosine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assertion (ARBA / ortholog-based) of sphingosine biosynthesis, matching the experimentally supported core process. Reason: Redundant electronic support for the experimentally established core BP. |
| GO:0046514 ceramide catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer (Ensembl Compara, from the mouse ortholog Q8R4X1) of ceramide catabolism, matching the experimentally supported core process. Reason: Redundant ortholog-based support for the experimentally established core BP. |
| GO:0048733 sebaceous gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from the mouse ortholog. ACER1 acts in epidermis and skin sphingolipid metabolism, but a specific, direct role in sebaceous gland development is not supported by the human experimental literature reviewed here; retained as a non-core skin-development association pending direct evidence. Reason: Ortholog-transferred developmental association with weak/indirect support; plausible given the skin-restricted expression but not part of the demonstrated core function. |
| GO:0030149 sphingolipid catabolic process | TAS Reactome:R-HSA-9845614 | KEEP AS NON CORE | Summary: Reactome places ACER1 in sphingolipid catabolism. Correct but a broad parent of the specific ceramide catabolic process that is the core BP; kept as non-core. Reason: General parent of the specific, experimentally supported ceramide catabolism term. |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-based mapping to sphingolipid metabolism (UPA00222). Correct but a broad grouping term; the specific ceramide-catabolism / sphingosine-biosynthesis children are the core processes. Reason: High-level pathway grouping; superseded by the specific catabolic/biosynthetic BPs. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | TAS Reactome:R-HSA-428231 | ACCEPT | Summary: Reactome (traceable author statement) of the core ceramidase activity of ACER1 at the ER membrane. Correct and consistent with experimental evidence. Reason: Curated statement of the core catalytic MF. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | ACCEPT | Summary: Experimental localization of ACER1 to the ER membrane. This is the precise core cellular location of this multi-pass membrane enzyme. Reason: Experimentally supported integral ER membrane localization; core CC. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IMP PMID:20207939 Role of alkaline ceramidases in the generation of sphingosin... | ACCEPT | Summary: Ceramidase activity inferred from mutant/knockdown phenotype (alkaline-ceramidase inhibitor D-e-MAPP blocked sphingosine/S1P generation). Supports the core MF at the alkaline-ceramidase family level. Reason: Experimental (IMP) support for the core ceramidase molecular function. |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:20207939 Role of alkaline ceramidases in the generation of sphingosin... | ACCEPT | Summary: Alkaline ceramidase activity is required for sphingosine (and S1P) generation; supports sphingosine biosynthesis as a core process. Reason: Experimental support for the core sphingosine-biosynthesis process. |
| GO:0046514 ceramide catabolic process | IMP PMID:20207939 Role of alkaline ceramidases in the generation of sphingosin... | ACCEPT | Summary: Ceramide breakdown by alkaline ceramidase activity, inferred from inhibitor/knockdown effects on sphingoid-base levels; supports ceramide catabolism as a core process. Reason: Experimental support for the core ceramide-catabolism process. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-428231 | ACCEPT | Summary: Reactome traceable statement of ER membrane localization, matching the experimental EXP annotation; core cellular location. Reason: Curated statement consistent with the experimental ER membrane localization. |
| GO:0005783 endoplasmic reticulum | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: Direct-assay localization to the endoplasmic reticulum. Correct; the more specific membrane term (GO:0005789) captures the integral-membrane core location, so this parent term is kept as non-core. Reason: Correct but a parent of the specific ER membrane location that is the core CC. |
| GO:0006665 sphingolipid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (from mouse ortholog Q8R4X1) of sphingolipid metabolism. Correct but a broad grouping term; the specific children are the core processes. Reason: High-level grouping term; superseded by the specific catabolic/biosynthetic BPs. |
| GO:0008544 epidermis development | IEP PMID:16477081 Differentiation-associated expression of ceramidase isoforms... | KEEP AS NON CORE | Summary: Expression-pattern (IEP) association: alkaline ceramidase-1 is epidermis-restricted and its activity rises with epidermal differentiation. This is physiological context in skin rather than the enzyme's core biochemical function; kept as non-core. Reason: Based on differentiation-associated expression correlation, not a demonstrated developmental mechanism; a downstream skin role, not the core function. |
| GO:0010446 response to alkaline pH | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: Captures the alkaline pH optimum (pH 8.0) of ACER1 activity. This describes the enzyme's biochemical property (alkaline ceramidase) rather than a cellular pH-response pathway; retained as non-core supporting context. Reason: Reflects the alkaline pH optimum of the ceramidase; peripheral to the core catabolic function. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | ACCEPT | Summary: Direct enzymatic assay: haCER1 hydrolyses very-long-chain ceramides to generate sphingosine (Ca2+-dependent). Primary experimental support for the core ceramidase molecular function of human ACER1. Reason: Direct-assay evidence for the core catalytic function. |
| GO:0030148 sphingolipid biosynthetic process | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: Annotated because ACER1 activity raises sphingosine and sphingosine-1-phosphate. ACER1's direct reaction is ceramide catabolism producing sphingosine; the downstream generation of S1P is a biosynthetic consequence, so this broader biosynthesis term is kept as non-core. Reason: Downstream/indirect biosynthetic effect; the specific direct process is sphingosine biosynthesis (GO:0046512), and the enzyme's direct action is catabolic. |
| GO:0030154 cell differentiation | IMP PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: ACER1 knockdown blocked the calcium-induced differentiation of human epidermal keratinocytes. A genuine downstream physiological role but broad; the specific keratinocyte-differentiation term is more informative. Kept as non-core. Reason: Generic differentiation term for a skin-specific role; superseded by keratinocyte differentiation and not the enzyme's core biochemical function. |
| GO:0030216 keratinocyte differentiation | IEP PMID:16477081 Differentiation-associated expression of ceramidase isoforms... | KEEP AS NON CORE | Summary: Alkaline ceramidase activity increases with keratinocyte differentiation (expression association). Consistent with the IMP knockdown phenotype in PMID:17713573; a downstream physiological role in skin, kept as non-core. Reason: Physiological skin role supported by expression correlation and knockdown; not the core biochemical function of the enzyme. |
| GO:0046512 sphingosine biosynthetic process | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | ACCEPT | Summary: Direct-assay evidence that ACER1 generates sphingosine from very-long-chain ceramides; core biological process. Reason: Direct product of the ceramidase reaction; experimentally demonstrated. |
| GO:0046514 ceramide catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of ceramide catabolism from the mouse ortholog, matching the experimentally supported core process. Reason: Redundant ortholog-based support for the experimentally established core BP. |
| GO:0071277 cellular response to calcium ion | IDA PMID:17713573 Upregulation of the human alkaline ceramidase 1 and acid cer... | KEEP AS NON CORE | Summary: ACER1 is a Ca2+-dependent, calcium-upregulated enzyme mediating the keratinocyte response to extracellular calcium. A real regulatory/physiological role, but peripheral to the core catabolic function; kept as non-core. Reason: Reflects Ca2+-dependence and Ca2+-induced upregulation; supporting regulatory context rather than the core molecular function. |
| GO:0017040 N-acylsphingosine amidohydrolase activity | IDA PMID:20628055 Alkaline ceramidase 2 (ACER2) and its product dihydrosphingo... | ACCEPT | Summary: Direct-assay support for the ceramidase molecular function (additional oleoyl/dihydroceramide substrates). Core molecular function. Reason: Direct-assay evidence for the core catalytic function. |
| GO:0046512 sphingosine biosynthetic process | IDA PMID:20628055 Alkaline ceramidase 2 (ACER2) and its product dihydrosphingo... | ACCEPT | Summary: Direct-assay support for generation of the sphingoid base (sphingosine / dihydrosphingosine) by alkaline ceramidase activity; core biological process. Reason: Direct product of the ceramidase reaction; experimentally demonstrated. |
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Download this section (compressed HTML)Q: Does ACER1 have a demonstrable, direct role in sebaceous gland development, or is the ortholog-transferred annotation an artefact of its skin-restricted expression?
Q: What is the in vivo consequence of ACER1 loss in human skin (barrier function, keratinocyte differentiation) beyond the cell-culture keratinocyte data?
Experiment: Lipidomic profiling (ceramide species, sphingosine, S1P) in ACER1-knockout vs wild-type human epidermal keratinocytes / reconstructed epidermis to quantify its contribution to the very-long-chain ceramide pool and barrier lipids.
Experiment: Determine the ACER1 substrate spectrum and pH/metal dependence with purified, reconstituted enzyme to define its precise preference among very-long-chain and unsaturated ceramides versus dihydroceramides.
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