Gene Ontology annotation through association of InterPro records with GO terms.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
Gene Ontology annotation based on curation of immunofluorescence data
Electronic Gene Ontology annotations created by ARBA machine learning models
Identification of a family of animal sphingomyelin synthases.
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Identified SMS1 and SMS2 as the two principal sphingomyelin synthases in animal cells with distinct subcellular localizations
"human, mouse and Caenorhabditis elegans genomes each contain at least two different SM synthase (SMS) genes. Whereas human SMS1 is localised to the Golgi, SMS2 resides primarily at the plasma membrane."
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Established distinct subcellular localizations: SMS1 in Golgi and SMS2 at plasma membrane
"Whereas human SMS1 is localised to the Golgi, SMS2 resides primarily at the plasma membrane."
Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER.
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SAMD8 produces only trace amounts of CPE (~300-fold less than SMS1-derived SM) despite having detectable CPES activity in vitro
"the CPE levels in HeLa or CHO-K1 cells are exceedingly low (∼0.03 mol%, i.e., 300-fold lower than SM; see Fig. 5 A)"
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Functions as a ceramide sensor: blocking SAMD8 causes marked ceramide accumulation in ER, leading to ER exit site fragmentation and Golgi collapse
"We propose that SMSr is a CPES with dual activity as ceramide sensor to control ceramide homeostasis in the ER and that the latter process is critical for the integrity of the early secretory pathway."
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Localizes specifically to ER membrane via N-terminal SAM domain; SAM domain removal causes redistribution to Golgi
"hSMSr-V5 gave a reticular and nuclear envelope staining pattern and colocalized with the ER marker protein disulfide isomerase"
SAMD8 transfers phosphatidyl from PE onto C16DH CER
Sphingomyelin synthase-related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease
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SAMD8 functions primarily as a phosphatidylethanolamine-specific phospholipase C (PE-PLC), hydrolyzing PE to generate DAG and phosphoethanolamine
"Sphingomyelin synthase-related protein SMSr is a phosphatidylethanolamine phospholipase C that promotes nonalcoholic fatty liver disease"
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SAMD8 deficiency attenuates high-fat diet/fructose-induced fatty liver and NASH by increasing hepatic PE levels
"We found that SMSr/PE-PLC deficiency attenuated high-fat diet/fructose-induced fatty liver and NASH, and attenuated glucosylceramide accumulation-induced NASH, fibrosis, and tumor formation."
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NASH patients show higher liver SAMD8 expression and lower plasma PE/PC ratios; PE levels negatively correlate with inflammatory markers
"plasma TNFα levels were negatively correlated with PE"
Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death
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SAMD8 is specifically cleaved by caspase-6 during apoptosis at conserved aspartate between SAM domain and first transmembrane span
"Treatment of cells with staurosporine resulted in proteolytic cleavage of SMSr-V5 but not of its caspase-resistant counterpart, SMSrCR-V5 (Figure 3C), hence confirming that Asp118 and Asp120 are the principle caspase cleavage sites in SMSr"
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Serves as negative regulator of ceramide-induced apoptosis; cleavage during apoptosis removes this protective function
"While this finding is in line with a role of SMSr as negative regulator of ceramide-induced cell death"
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High brain expression raises potential involvement in neurodegenerative disorders where caspase-6 is implicated
"As SMSr constitutes the principle CPE synthase in brain [38], it would be of interest to explore whether its proteolytic cleavage by caspase-6 has any relevance in the pathogenesis of neurodegenerative diseases"
ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain
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SAM domain mediates homotypic oligomerization essential for ER retention; mutations disrupting oligomerization cause Golgi mislocalization
"Residues critical for DGKδ-SAM oligomerization are conserved in SMSr-SAM and their substitution causes a dissociation of SMSr oligomers as well as a partial redistribution of the enzyme to the Golgi"
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SAMD8 forms trimers/hexamers in ER membrane via SAM-SAM domain contacts, creating clustering recognized by cellular retention mechanisms
"From this we conclude that SMSr-SAM mediates self-assembly of SMSr into trimers and hexamers in the ER"
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SAM domain structure resembles that of diacylglycerol kinase delta, suggesting potential cross-talk between DAG/PA and ceramide signaling pathways
"Here we report that SMSr-SAM is structurally and functionally related to the SAM domain of diacylglycerol kinase DGKδ, a central regulator of lipid signaling at the plasma membrane"
Diacylglycerol kinase δ and sphingomyelin synthase-related protein functionally interact via their sterile α motif domains.
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SMSr (SAMD8) physically interacts with DGKδ through their SAM domains; SMSr-SAMD but not SMS1-SAMD co-immunoprecipitates with DGKδ-SAMD
"In this study, we found that SMSr-SAMD, but not SMS1-SAMD, co-immunoprecipitates with DGKδ-SAMD."
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SMSr acts as a candidate diacylglycerol-providing enzyme upstream of DGKδ, supplying 16:0/16:1-containing DAG that DGKδ converts to PA in a pathway independent of phosphatidylinositol turnover
"We found that SMSr overexpression significantly enhances the production of 16:0- or 16:1-containing PA species such as 14:0/16:0-, 16:0/16:0-, 16:0/18:1-, and/or 16:1/18:1-PA in DGKδ-overexpressing COS-7 cells."
Sphingomyelin Synthase Family and Phospholipase Cs.
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SMSr (SAMD8) is the third SMS-family member, an ER-localized six-transmembrane protein with a conserved His-His-Asp catalytic triad that lacks SM synthase activity but has in vitro CPE synthase activity
"unlike SMS1 and SMS2, SMSr does not have SM synthase activity but instead catalyzes synthesis an SM analog, ceramide phosphoethanolamine (CPE), in test tubes"
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SMSr is a specific PE-PLC rather than a pan-PLC; recombinant SMSr lacks PC-PLC, PS-PLC, PG-PLC and PAP activities, and its PE-PLC activity is calcium-independent and inhibited by D609
"SMSr is a specific PE-PLC but not a pan-PLC and its specificity is an important property of SMSr"
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Smsr knockout mice are fertile with only marginal changes in extremely low CPE levels and unchanged ceramide, raising the question of whether CPE synthesis is the true biological function of SMSr
"quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE levels which were extremely low"
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SMSr ER residency relies on SAM-domain-mediated homotypic oligomerization, and SMSr functionally interacts with DGKδ via their SAM domains, linking SMSr to glycerophospholipid metabolism beyond sphingolipids
"SMSr’s ER residency relies on homotypic oligomerization mediated by its SAM domain (59)"
Falcon (Edison) deep research on SAMD8/SMSr function
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SMSr is an ER-resident multi-pass membrane enzyme of the sphingomyelin synthase family whose SAM domain controls oligomerization and ER retention; recent work reframes it as a PE-PLC regulating hepatic PE and DAG signaling
"Historically, SMSr has been studied as a **ceramide phosphoethanolamine (CPE) synthase** (a “trace” phosphosphingolipid pathway), but recent work (2023) argues that in vivo its dominant role may be **phosphatidylethanolamine phospholipase C (PE‑PLC)** activity that regulates hepatic PE levels and promotes NAFLD/NASH phenotypes."
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SMSr interacts with DGKδ via its SAM domain, contributing DAG that DGKδ converts into defined PA species, defining a ceramide-independent DAG-to-PA signaling axis
"SMSr contributes to **DAG generation** (via PLC-like chemistry), which is then converted by DGKδ into defined PA species"
Deep research on SAMD8 function
Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis.
Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide.
Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis.
Sphingomyelin synthase-related protein is a regulator of serine palmitoyltransferase.
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Human liver/adipose datasets show SMSr/SPT coexpression without establishing causal direction.
"the directionality of the relationship cannot easily be assessed with observational human RNA-seq data."
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Mouse liver microsomal PE supplementation reduces SPT activity, and tagged SMSr co-immunoprecipitates with SPTLC2; these assays complement high-fat-diet knockout and overexpression phenotypes.
"We found that PE supplementation significantly reduced SPT activity in a dose-dependent fashion (Fig. 5D)."
Sphingomyelin synthase related protein is a mammalian phosphatidylethanolamine phospholipase C.
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Direct human recombinant assays support PE-PLC but do not detect sphingomyelin synthesis under their conditions.
"Indeed, rSMSr produced NBD-CPE (Fig. 3A) but not NBD-SM (Fig. 3B)."
OpenScientist focused SAMD8 reaction-spectrum, pathway and compartment report
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Report recognizes the measured PE-dependent CPE chemistry, although its GO:0002950 recommendation specifies a different donor.
"transfer of phosphoethanolamine from PE onto ceramide"
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The report did not access the 2024 mechanistic study needed to resolve residual wild-type SMS activity.
"Two of the three UniProt-cited PLC papers (PMID 34332077, 38388831) were not retrievable"
SAMD8 reaction donor, PAINT and focused-report assessment