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Showing SMPD3 — NSMASE2 is a alias.

SMPD3

Sphingomyelin phosphodiesterase 3 · UniProt Q9NY59

Length
655 aa
Mass
71.1 kDa
Annotated
2026-06-10
62 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMPD3 (nSMase2) is a Mg2+-dependent, membrane-associated neutral sphingomyelinase that hydrolyzes sphingomyelin to ceramide, and is the principal neutral sphingomyelinase active in postnatal development (PMID:15764706, PMID:15059969). Its catalytic domain adopts a DNase-I-type fold whose active site is gated by a conserved 'DK switch'; catalysis requires an allosteric interaction with the membrane-anchored N-terminal domain via a juxtamembrane region, and a conserved Asp in the DK switch is essential for activity, allosteric activation, phosphatidylserine stimulation, and GW4869 inhibition (PMID:28652336). The ceramide and diacylglycerol generated by SMPD3 in the Golgi SMPD3–SMS1 compartment serve as fusogenic intermediates required for secretory vesicle formation; loss of these lipids in smpd3-deficient cells impairs Golgi vesicle transport and drives dysproteostasis, ER stress, and apoptosis, arresting extracellular matrix secretion in chondrocytes and proteo-hormone secretion in hypothalamic neurons (PMID:15764706, PMID:27882938). This secretory function makes SMPD3 enzymatic activity essential for endochondral bone and dentin mineralization, where its loss causes osteogenesis/dentinogenesis imperfecta-like skeletal disease in mice (PMID:16025116, PMID:27325675). At the plasma membrane, ceramide enrichment by SMPD3 supports extracellular vesicle/exosome biogenesis that mediates intercellular transfer of cargo including miRNAs, tau, and α-synuclein (PMID:23439645, PMID:31555088, PMID:38049923), although a genetic knockout study found EV release to be cell-type-specific rather than universally SMPD3-dependent (PMID:39525277). SMPD3 is acutely activated downstream of TNF-α through p38 MAPK and PKC-delta, which control its Golgi-to-plasma-membrane translocation, and is held in check by direct binding of calcineurin, which dephosphorylates and inactivates it (PMID:17085432, PMID:18653803, PMID:20106976). Transcriptionally, SMPD3 is driven by Runx2, SOX9/SOX10, retinoic-acid-receptor-mediated histone acetylation via CBP/p300, and HIF-1α in tissue-specific contexts (PMID:19250608, PMID:38052296, PMID:27013100, PMID:40404566).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 Medium

    Establishing that nSMase2 is a genuine cellular enzyme answered whether the cloned protein generates ceramide in situ and where it acts.

    Evidence Heterologous adenoviral expression in rat hepatocytes with in vitro SMase assay, ceramide measurement, and immunofluorescence

    PMID:15059969

    Open questions at the time
    • Localization to plasma membrane only in overexpression context
    • Mg2+ dependence shown biochemically but native regulation unaddressed
  2. 2005 High

    Knockout and positional-cloning studies established SMPD3 as the dominant postnatal neutral sphingomyelinase and tied its enzymatic loss to defined developmental phenotypes.

    Evidence smpd3−/− mice and fro/fro mutant with SMase activity assays, subcellular fractionation, and skeletal/endocrine phenotyping

    PMID:15764706 PMID:16025116

    Open questions at the time
    • Molecular link between Golgi ceramide and secretory defect not yet mechanistic
    • Bone mineralization mechanism unresolved at this stage
  3. 2006 High

    Identifying TNF-α-driven p38 MAPK control of nSMase2 translocation answered how the enzyme is acutely mobilized in inflammatory signaling.

    Evidence Fluorescence microscopy of translocation, in vitro N-SMase activity, and pharmacological p38/ERK/JNK inhibition in A549 cells

    PMID:17085432

    Open questions at the time
    • Direct effector linking p38 to nSMase2 not identified
    • Translocation target compartment defined only as plasma membrane
  4. 2008 Medium

    PKC-delta was placed as a second, p38-independent regulator of nSMase2 translocation, refining the signaling architecture of activation.

    Evidence PKC inhibitors, siRNA of PKC isoforms, translocation microscopy, activity assay, and negative co-IP

    PMID:18653803

    Open questions at the time
    • Regulation inferred to be indirect; no direct PKC-delta–nSMase2 interaction
    • Intermediate effector between PKC-delta and translocation unknown
  5. 2010 High

    Discovery that calcineurin directly binds and dephosphorylates nSMase2 established a phosphorylation on/off switch coupling oxidative stress to enzyme activity.

    Evidence Serine-phospho analysis, calcineurin co-IP, calcineurin-binding-site mutant, and activity assays

    PMID:20106976

    Open questions at the time
    • Kinase responsible for the activating phosphorylation not identified
    • Specific phosphoserine sites not mapped
  6. 2011 Medium

    Isoform-specificity and cholesterol/eNOS work showed nSMase2 is the chief TNF-responsive N-SMase and a regulator of membrane lipid homeostasis beyond ceramide.

    Evidence siRNA/overexpression of nSMase isoforms with mass-spec lipid measurement; reciprocal OE/KD in endothelial cells with cholesterol and NO readouts

    PMID:21303347 PMID:22063270

    Open questions at the time
    • Mechanism linking ceramide to cholesterol redistribution unresolved
    • Post-transcriptional TNF-α induction mechanism undefined
  7. 2013 Medium

    Linking nSMase2 to exosomal miRNA secretion and to ischemic astrocyte inflammation extended its role from intracellular trafficking to intercellular signaling.

    Evidence nSMase2 knockdown/overexpression with exosome isolation and miRNA transfer assays; ischemia models with nSMase2–RACK1/EED co-IP and p38/A2BAR pharmacology

    PMID:23439645 PMID:24007266

    Open questions at the time
    • RACK1/EED interaction functional consequence not resolved
    • Whether ceramide directly nucleates exosomal cargo loading untested
  8. 2016 High

    Defining the SMPD3-SMS1 sphingomyelin–ceramide–DAG cycle and tissue-specific genetic dissection established the mechanism by which SMPD3 loss disrupts the secretory pathway and bone development.

    Evidence smpd3−/− mice and chondrocytes with lipidomics and UPR markers; conditional Cre-loxP knockouts and transgenic rescue; ATRA/CBP/p300 transcriptional analysis

    PMID:27013100 PMID:27325675 PMID:27882938

    Open questions at the time
    • Identity of vesicle-budding machinery sensing ceramide/DAG unknown
    • How epigenetic regulation integrates with developmental signals unresolved
  9. 2017 High

    The crystal structure resolved the catalytic mechanism, revealing the DNase-I fold, the DK-switch gate, and allosteric activation by the membrane-anchored NTD.

    Evidence 1.85-Å crystal structure with active-site mutagenesis and reconstitution of allosteric activation

    PMID:28652336

    Open questions at the time
    • Full-length membrane-embedded structure not solved
    • Conformational dynamics of DK-switch in vivo not captured
  10. 2018 Medium

    Connecting SMPD3 to tumor apoptotic responses, AML/ALL mutations, and skeletal/dental developmental signaling broadened its disease relevance and identified druggable inhibition of the DK switch.

    Evidence SMPD3 reconstitution and TNF viability assays with disease-mutant stability/localization analysis; cambinol enzyme/EV/tau assays with docking; inducible chondrocyte knockout fracture model

    PMID:18299447 PMID:29604274 PMID:30530524

    Open questions at the time
    • Whether AML/ALL mutations are driver events untested
    • In vivo selectivity of cambinol for the DK switch not confirmed structurally
  11. 2019 Medium

    Pharmacological and genetic inhibition established nSMase2-dependent EV biogenesis as a conserved route for spread of pathogenic proteins and viruses and for vascular inflammation.

    Evidence GW4869 and siRNA studies of α-syn and ZIKV transfer; Apoe−/−;Smpd3 atherosclerosis model with Nrf2 epistasis; AD-like phenotype in smpd3−/− neurons

    PMID:29725009 PMID:29794115 PMID:30866785 PMID:31555088

    Open questions at the time
    • α-syn work lacks genetic confirmation
    • Mechanism linking ceramide EVs to Nrf2 activation undefined
  12. 2023 Medium

    In vivo inhibitor work and additional structural/transcriptional studies confirmed ceramide-driven EV-mediated tau propagation and mapped further regulatory inputs to SMPD3.

    Evidence PS19 tauopathy and tau-propagation models with selective nSMase2 inhibitor PDDC; DPTIP/H463A DK-switch mutagenesis with antiviral assays; SOX9/SOX10 ChIP-seq and enhancer analysis; Shh-Gli1 odontoblast study

    PMID:36430407 PMID:38049923 PMID:38052296 PMID:40639673

    Open questions at the time
    • Whether plasma EV pTau is a faithful biomarker of brain activity not established
    • His463 allosteric cavity not structurally resolved with bound inhibitor
  13. 2024 Medium

    Proximity proteomics and a rigorous knockout challenged the universality of nSMase2-driven EV release, defining its trafficking proximitome while revealing cell-type-specific dependence.

    Evidence APEX2 proximity labeling in Jurkat cells with TNFα stimulation; CRISPR/Cas9 Smpd3 knockout mice with in vitro/in vivo EV quantification and Alix comparison

    PMID:39044828 PMID:39525277

    Open questions at the time
    • Direct binding partners within the proximitome not validated
    • Determinants of cell-type EV dependence unidentified
  14. 2025 Medium

    Stress-coupled regulation studies linked mitochondrial damage and HIF-1α transcription to SMPD3 activation in neuronal EV release and hepatic lipid handling.

    Evidence TIRF imaging of glucocorticoid-induced sEV release with nSMase2/Rab27a knockdown and mPTP/ROS dissection; HIF-1α ChIP and liver-specific knockdown with ceramide readout

    PMID:40404566 PMID:42059363

    Open questions at the time
    • Mechanism coupling mitochondrial ROS/mPTP to nSMase2 activation undefined
    • Direct vs indirect HIF-1α binding site not mapped at base resolution

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which cell types and physiological contexts genuinely require SMPD3 for EV biogenesis versus secretory trafficking, and what kinase and effector machinery couple upstream signals to its activation and vesicle budding.
  • Cell-type determinants of EV dependence unknown
  • Activating kinase and ceramide-sensing budding machinery unidentified
  • Full-length membrane-embedded structure and in-cell DK-switch dynamics unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005794 Golgi apparatus 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CALCINEURINEEDRACK1SMS1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Crystal structure of the human nSMase2 catalytic domain resolved at 1.85-Å reveals a DNase-I-type fold with a hydrophobic track leading to the active site blocked by an evolutionarily conserved 'DK switch' motif. The soluble catalytic domain directly interacts with the membrane-associated N-terminal domain (NTD), which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region linking NTD and catalytic domain is necessary and sufficient for activation. Mutation of the conserved Asp residue in the DK switch disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and inhibition by GW4869. Crystal structure (1.85 Å), active-site mutagenesis, in vitro enzyme activity assays, reconstitution of allosteric activation Proceedings of the National Academy of Sciences of the United States of America High 28652336
2005 SMPD3 is the primary neutral sphingomyelinase active in postnatal development; smpd3−/− mice are devoid of neutral sphingomyelinase activity and develop dwarfism and delayed puberty caused by hypothalamus-induced combined pituitary hormone deficiency. SMPD3 is segregated into detergent-resistant subdomains of Golgi membranes of hypothalamic neurosecretory neurons, where its transient activation modifies the lipid bilayer as an essential step in the Golgi secretory pathway. Knockout mouse generation (smpd3−/− and smpd2−/−smpd3−/− double mutant), biochemical SMase activity assay, subcellular fractionation into detergent-resistant membrane domains Proceedings of the National Academy of Sciences of the United States of America High 15764706
2005 A deletion in the Smpd3 gene (fragilitas ossium mutation) results in complete loss of SMPD3 enzymatic activity and causes a syndrome of osteogenesis and dentinogenesis imperfecta in mice without detectable collagen defect, establishing SMPD3's enzymatic activity as essential for bone and dentin mineralization. Positional cloning, enzymatic activity assay confirming loss of activity in fro/fro mice Nature genetics High 16025116
2016 SMPD3 deficiency disrupts homeostasis of the sphingomyelin–ceramide–diacylglycerol cycle in the Golgi SMPD3-SMS1 compartment. Loss of the fusogenic lipid intermediates ceramide and DAG impairs vesicle formation and transport in the Golgi secretory pathway, causing dysproteostasis, unfolded protein response, ER stress, and apoptosis. In chondrocytes this arrests secretion of extracellular matrix proteins causing skeletal malformation; in hypothalamic neurons it retards proteo-hormone secretion. smpd3−/− mouse and derived primary chondrocytes; lipidomics (SM, Cer, DAG quantification); immunofluorescence; assessment of UPR/ER stress markers Cell death & disease High 27882938
2006 TNF-α stimulates acute translocation of nSMase2 from a basal location to the plasma membrane of A549 epithelial cells in a time- and dose-dependent manner, and rapidly increases N-SMase activity. This translocation is regulated by p38-alpha MAPK (but not ERK or JNK); p38 MAPK inhibition abrogates the TNF-α-induced increase in endogenous N-SMase activity. Both p38-alpha MAPK and nSMase2 are required for TNF-α-stimulated up-regulation of VCAM-1 and ICAM-1, largely independently of NF-κB. Fluorescence microscopy (translocation), in vitro N-SMase activity assay, pharmacological p38/ERK/JNK inhibitors, nSMase2 overexpression The Journal of biological chemistry High 17085432
2008 PKC-delta mediates TNF-α- and PMA-stimulated translocation of nSMase2 from the Golgi to the plasma membrane. PKC-delta acts independently of p38 MAPK for translocation, but does not regulate in vitro N-SMase activity, and PKC-delta and nSMase2 do not co-immunoprecipitate, suggesting indirect regulation. PKC-delta is upstream of nSMase2-dependent induction of VCAM-1 and ICAM-1. Pharmacological PKC inhibitors, siRNA knockdown of PKC isoforms, fluorescence microscopy of nSMase2 translocation, in vitro N-SMase activity assay, co-immunoprecipitation (negative for direct interaction) Molecular pharmacology Medium 18653803
2010 nSMase2 is a phosphoprotein phosphorylated exclusively at serine residues. Calcineurin (PP2B) binds directly to nSMase2 and acts as an on/off switch for its phosphorylation: under oxidative stress, calcineurin is inhibited/degraded, releasing nSMase2 from dephosphorylation, resulting in elevated phosphorylation and increased enzymatic activity. A mutant lacking the calcineurin-binding site shows constitutively elevated phosphorylation and activity that no longer responds to oxidative stress. Phospho-protein analysis (serine-specific), co-immunoprecipitation of calcineurin with nSMase2, calcineurin inhibitors/siRNA, active-site binding-site mutant, in vitro N-SMase activity assay The Journal of biological chemistry High 20106976
2004 Heterologous expression of mouse NSMase2 in primary rat hepatocytes generates a Mg2+-dependent, EDTA-inhibited and Triton-inhibited neutral sphingomyelinase that increases cellular ceramide levels, demonstrating in situ enzymatic activity. FLAG-tagged NSMase2 localizes to the plasma membrane by immunofluorescence. NSMase2 expression potentiates IL-1β-induced JNK phosphorylation via a PP2A-family phosphatase, possibly by modulating phosphorylation of IRAK. Adenovirus-mediated gene transfer, in vitro SMase activity assay, ceramide measurement, immunofluorescence localization, JNK phosphorylation assay, PP2A family phosphatase involvement FASEB journal Medium 15059969
2011 nSMase2 is the primary TNF-α-responsive N-SMase isoform in MCF-7 cells; TNF-α induces late increases in N-SMase activity through post-transcriptional mechanisms. Overexpression of nSMase2 (but not nSMase1 or nSMase3) significantly increases cellular ceramide and decreases sphingomyelin. siRNA knockdown of nSMase2 (but not nSMase3) inhibits TNF-α-induced N-SMase activity. siRNA knockdown, overexpression, in vitro N-SMase activity assay, cellular sphingolipid measurement by mass spectrometry The Biochemical journal Medium 21303347
2013 nSMase2 (nSMase2/SMPD3) regulates exosomal microRNA secretion from cancer cells; its activity is required for exosome-mediated transfer of miR-210 to endothelial cells, which suppresses specific target genes to enhance angiogenesis and promote metastasis. nSMase2 knockdown/overexpression in cancer cells, exosome isolation, miRNA profiling, functional angiogenesis and metastasis assays in tumor models The Journal of biological chemistry Medium 23439645
2018 Reconstitution of SMPD3 expression in mouse tumor cells lacking the endogenous gene enhances TNF-induced reduction of cell viability, and mutations found in human leukemia AML/ALL cases cause defects in SMPD3 protein stability and localization, demonstrating that SMPD3 function (ceramide pathway) contributes to apoptotic responses in hematopoietic tumor cells. SMPD3 reconstitution in tumor cell lines, cell viability assay with TNF treatment, sequencing of mutants with functional analysis of stability and localization Blood Medium 18299447
2013 In rat hippocampal ischemia, nSMase2 (but not aSMase) activity is induced early in astrocytes (not neurons), driving ceramide accumulation and production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Enhanced binding of nSMase2 with RACK1 and EED is observed post-ischemia. nSMase2 activation is mediated by p38 MAPK downstream of A2B adenosine receptor, and is not blocked via the RACK1/EED/TNF-α receptor pathway. Four-vessel occlusion and OGD ischemia models, immunoprecipitation (nSMase2 with RACK1/EED), SMase activity assay, p38 MAPK inhibition, A2BAR pharmacology, cytokine mRNA quantification Journal of neuroinflammation Medium 24007266
2016 Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development. Transgenic rescue of Smpd3 in chondrocytes of fro/fro mice corrects cartilage but not bone abnormalities; conditional knockout in Osx-expressing cells (chondrocytes + osteoblasts) recapitulates the full fro/fro skeletal phenotype. PTHrP downregulates Smpd3 expression in chondrogenic cells through transcription factor SOX9. Cre-loxP conditional knockout (Col2a1-Cre and Osx-Cre), transgenic rescue, quantitative histology and bone analysis, gene expression analysis in ATDC5 cells Molecular and cellular biology High 27325675
2009 BMP2 stimulation upregulates smpd3 mRNA expression in C2C12 cells and the transcription factor Runx2 directly binds to Runx2-responsive elements (RRE) in the smpd3 promoter (at -562 to -557 and -355 to -350 regions) to activate its transcription. BMP2 treatment and Runx2 transfection in C2C12 cells, promoter-reporter assay, EMSA (electrophoretic mobility shift assay) BMB reports Medium 19250608
2016 ATRA regulates nSMase2 transcriptionally through retinoic acid receptor-α via modulation of histone acetylation, independent of Sp1/Sp3/Runx2 and without increased promoter activity. HDAC inhibition with TSA induces nSMase2 comparably to ATRA. The histone acetyltransferases CBP and p300 are required for ATRA-induced nSMase2 expression. HDAC4 and/or HDAC5 act as negative transcriptional regulators of nSMase2. HDAC inhibitors, siRNA knockdown of CBP/p300/HDACs, reporter assays, RT-qPCR, chromatin analysis Journal of lipid research Medium 27013100
2018 SMPD3 deficiency in neuronal Golgi compartment impairs vesicular protein transport, causing accumulation of APP, Aβ, and phosphorylated Tau, dysproteostasis, UPR, and apoptosis in smpd3−/− mouse neurons, resulting in progressive cognitive decline with AD-like signatures. smpd3−/− mouse model, immunoblotting for APP/Aβ/pTau, UPR markers, cognitive/behavioral testing, Golgi transport assays Cell death & disease Medium 29725009
2011 ER stress inhibits NSMase2 activity and elevates plasma membrane and intracellular cholesterol in endothelial cells. NSMase2 knockdown decreases eNOS phosphorylation and NO production by ~50% and ~40% respectively, while increasing PM cholesterol. NSMase2 overexpression in ER-stressed cells restores cholesterol to near-control levels and recovers NO production to ~68–74% of controls, establishing NSMase2 as a pivotal regulator of cholesterol homeostasis and eNOS activation. NSMase2 overexpression and knockdown in BAEC, cholesterol measurement (epifluorescence and cholesterol oxidase), eNOS phosphorylation assay, NO production measurement Biochimica et biophysica acta Medium 22063270
2019 ZIKV infection induces both activity and gene expression of nSMase2/SMPD3 in cortical neurons. Silencing of SMPD3 reduces viral burden and exosome-mediated transmission of ZIKV. GW4869 (nSMase2 inhibitor) reduces ZIKV loads in neurons and in exosomes derived from these cells. SMPD3 siRNA knockdown, pharmacological inhibition (GW4869), exosome isolation, viral load quantification (qPCR), cryo-EM of neuronal exosomes Emerging microbes & infections Medium 30866785
2018 Cambinol inhibits nSMase2 enzyme activity in dose-responsive fashion and suppresses extracellular vesicle production, thereby reducing tau seed propagation in vitro. In vivo oral administration of cambinol reduces nSMase2 activity in the brain. Molecular docking analysis suggests cambinol targets the DK-switch in the nSMase2 active site. In vitro nSMase2 enzyme activity assay, EV production assay, tau propagation assay, oral in vivo dosing with brain activity measurement, molecular docking Biochemical and biophysical research communications Medium 29604274
2019 nSMase2 inhibition with GW4869 decreases transfer of oligomeric α-synuclein between neuron-like cells and reduces accumulation and aggregation of high-molecular-weight α-syn, establishing nSMase2-dependent EV biogenesis as a route for α-syn propagation. GW4869 pharmacological inhibition, α-syn transfer assay between neuron-like cells, western blot for α-syn aggregates Frontiers in molecular neuroscience Medium 31555088
2018 nSMase2 deficiency or GW4869 pharmacological inhibition reduces atherosclerotic lesion development in Apoe−/− mice. The anti-inflammatory mechanism involves Nrf2 activation in endothelial cells and macrophages: GW4869 fails to protect when Nrf2 is silenced by siRNA in endothelial cells and is ineffective in LPS-stimulated macrophages from Nrf2-KO mice. Apoe−/−;Smpd3 genetic mouse model, GW4869 pharmacological inhibition, Nrf2 siRNA knockdown in endothelial cells, macrophages from Nrf2-KO mice, inflammatory gene expression (MCP-1, ICAM-1, VCAM-1 mRNA) Arteriosclerosis, thrombosis, and vascular biology Medium 29794115
2019 Postnatal ablation of Smpd3 causes impaired extracellular matrix mineralization and defective chondrocyte apoptosis at fracture sites. BMP-2 positively regulates Smpd3 expression via p38 MAPK in ATDC5 chondrogenic cells, while PTHrP negatively regulates Smpd3 expression, establishing opposing upstream regulators of SMPD3 in chondrocytes. Inducible conditional Smpd3 knockout (Smpd3flox/flox; Osx-Cre), tibial fracture model, p38 MAPK inhibition, gene expression analysis Molecular and cellular biology Medium 30530524
2023 Human tau expression in PS19 transgenic mice elevates brain ceramide levels and nSMase2 activity. The selective nSMase2 inhibitor PDDC normalizes both, reduces tau immunostaining, hippocampal neuronal layer thinning, glial activation, and lowers pTau-carrying neuronal-derived EVs in plasma. In a direct tau propagation model, PDDC blocks contralateral spread of tau, confirming nSMase2-generated ceramide drives EV-mediated tau propagation. Transgenic PS19 mouse model, nSMase2 activity assay, ceramide/sphingomyelin measurement, AAV tau-propagation model, immunohistochemistry, plasma EV isolation and pTau quantification, PDDC oral treatment Translational neurodegeneration Medium 38049923
2017 In murine TLR signaling models of SLE, TLR activation induces abnormal expression of SMPD3 and triggers its translocation from the Golgi apparatus. SMPD3 dysfunction in turn enhances TLR-induced inflammatory responses in B cells and macrophages. Immunofluorescence of SMPD3 Golgi localization and redistribution, gene expression analysis, B cell and macrophage functional assays with TLR stimulation Scandinavian journal of immunology Low 28889482
2023 DPTIP, a non-competitive inhibitor of nSMase2, blocks the DK-switch mechanism. Mutation of His463 in nSMase2 reduces DPTIP inhibitory activity, identifying His463 as a crucial residue in the allosteric inhibitory cavity. DPTIP shows antiviral activity against WNV (EC50 0.26 µM) and ZIKV (EC50 1.56 µM) through nSMase2 inhibition. In vitro nSMase2 activity assay with DPTIP, site-directed mutagenesis of H463A, computational docking, antiviral assay in cell culture International journal of molecular sciences Medium 36430407
2023 SMPD3 expression in odontoblasts is regulated by the Shh-Gli1 pathway: Smpd3 knockdown impairs odontoblast differentiation and reduces Dspp/Dmp1 markers, while Smpd3 overexpression enhances dentinogenic differentiation and promotes dentin formation ex vivo in a Shh-dependent manner. siRNA knockdown and overexpression in mDPCs, bulk RNA sequencing, Shh pathway inhibition, tooth germ culture, mineralization assays Bone Medium 40639673
2023 SOXE-family transcription factors SOX9 and SOX10 directly regulate SMPD3 expression in migrating neural crest cells via enhancer sequences in the first intron of the SMPD3 locus. ChIP-seq and nascent transcription analysis confirm that SOX10 directly drives expression of an SMPD3 enhancer specific to migratory neural crest cells. Enhancer-reporter assay, transcription factor knockdown, ChIP-seq, nascent transcription analysis (GRO-seq or equivalent), in vivo chick/Xenopus neural crest models Developmental biology Medium 38052296
2012 NSMase2 (fro/fro) deficiency leads to accumulation of sphingomyelin and dramatic reduction of ceramides in fibroblasts, and causes slow growth with G1/G0 arrest that is corrected by smpd3 transfection, indicating NSMase2 generates ceramides required for cell cycle progression. ASMase mRNA, protein and activity are substantially elevated in fro/fro fibroblasts, suggesting compensatory upregulation; ASMase deficiency does not affect NSMase2 activity. fro/fro and ASMase−/− mutant mouse fibroblasts, sphingolipid measurement, SMase activity assay, cell cycle analysis, smpd3 transfection rescue FEBS letters Medium 23046545
2024 Proximity labeling (APEX2) of nSMase2 in Jurkat cells reveals a plasma membrane proximal protein network that undergoes significant dynamic remodeling within the first 5 minutes of TNFα stimulation. The recruitment of most proximal proteins depends on nSMase2 enzymatic activity. Proteins related to vesicle-mediated transport (recycling endosomes, trans-Golgi network, exocytic vesicles) are significantly enriched in the proximitome of enzymatically active nSMase2 upon TNFα stimulation. APEX2 proximity labeling, streptavidin affinity purification, quantitative mass spectrometry, nSMase2-APEX2 stable cell line Frontiers in immunology Medium 39044828
2025 Glucocorticoids stimulate sEV secretion in neuronal cells through nSMase2 and Rab27a. GC-induced sEV release requires mitochondrial reactive oxygen species production and opening of the mitochondrial permeability transition pore (mPTP) upstream of nSMase2 activation, linking mitochondrial damage to ceramide-driven EV biogenesis. TIRF microscopy with mCh-CD63-pHluorin pH-sensitive sEV marker, Rab27a and nSMase2 knockdown, mPTP inhibitors, ROS measurement Journal of cell science Medium 42059363
2025 HIF-1α is identified as a direct transcriptional activator of SMPD3 in hepatocytes during alcohol-associated liver disease: ChIP assay demonstrates HIF-1α binding to the SMPD3 locus, and liver-specific Hif1α knockdown reduces hepatic SMPD3 expression. Silencing SMPD3 alleviates alcohol-induced lipid accumulation in hepatocytes. ChIP assay (HIF-1α at SMPD3 locus), liver-specific Hif1α knockdown mouse, SMPD3 siRNA in hepatocytes, ceramide measurement Journal of agricultural and food chemistry Medium 40404566
2024 CRISPR/Cas9-generated heterozygous full-body and conditional Smpd3 knockout mice show no impact of Smpd3 deficiency on EV release in vitro or in vivo, challenging the view that nSMase2 universally drives EV biogenesis and suggesting a cell-type-specific role. Bone marrow-derived macrophages show reduced EV release only upon Alix deletion, not Smpd3 deletion. CRISPR/Cas9 Smpd3 knockout mice (full-body and conditional), in vitro and in vivo EV quantification, Alix deletion comparison Journal of extracellular biology Medium 39525277

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. The Journal of biological chemistry 630 23439645
2017 Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artificial cells, nanomedicine, and biotechnology 238 29141446
2005 Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proceedings of the National Academy of Sciences of the United States of America 140 15764706
2005 A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nature genetics 137 16025116
2019 Exosomes mediate Zika virus transmission through SMPD3 neutral Sphingomyelinase in cortical neurons. Emerging microbes & infections 108 30866785
2018 nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe-/- Mice. Arteriosclerosis, thrombosis, and vascular biology 94 29794115
2006 Role for neutral sphingomyelinase-2 in tumor necrosis factor alpha-stimulated expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells: p38 MAPK is an upstream regulator of nSMase2. The Journal of biological chemistry 94 17085432
2017 Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. Proceedings of the National Academy of Sciences of the United States of America 91 28652336
2004 Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat hepatocytes modulates IL-beta-induced JNK activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 75 15059969
2008 Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 71 18299447
2013 Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi. Journal of neuroinflammation 68 24007266
2006 Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochimica et biophysica acta 65 16938269
2008 Regulation of neutral sphingomyelinase-2 (nSMase2) by tumor necrosis factor-alpha involves protein kinase C-delta in lung epithelial cells. Molecular pharmacology 64 18653803
2010 Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B). The Journal of biological chemistry 56 20106976
2021 Nipping disease in the bud: nSMase2 inhibitors as therapeutics in extracellular vesicle-mediated diseases. Drug discovery today 52 33798648
2016 Inhibiting Extracellular Vesicle Release from Human Cardiosphere Derived Cells with Lentiviral Knockdown of nSMase2 Differentially Effects Proliferation and Apoptosis in Cardiomyocytes, Fibroblasts and Endothelial Cells In Vitro. PloS one 48 27806113
2011 Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-α in MCF-7 cells. The Biochemical journal 47 21303347
2019 Inhibition of nSMase2 Reduces the Transfer of Oligomeric α-Synuclein Irrespective of Hypoxia. Frontiers in molecular neuroscience 41 31555088
2016 Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition. Cell death & disease 37 27882938
2024 Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice. Journal of advanced research 33 38582300
2016 Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development. Molecular and cellular biology 30 27325675
2021 Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model. Molecular brain 28 33875010
2018 Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2. Biochemical and biophysical research communications 28 29604274
2015 Abnormal methylation status of FBXW10 and SMPD3, and associations with clinical characteristics in clear cell renal cell carcinoma. Oncology letters 25 26722292
2018 SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment. Cell death & disease 23 29725009
2009 Upregulation of smpd3 via BMP2 stimulation and Runx2. BMB reports 23 19250608
2023 Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model. Translational neurodegeneration 21 38049923
2022 α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting. Journal of physiology and biochemistry 19 35984620
2019 Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression. Molecular and cellular biology 18 30530524
2017 TLR-Induced SMPD3 Defects Enhance Inflammatory Response of B Cell and Macrophage in the Pathogenesis of SLE. Scandinavian journal of immunology 18 28889482
2011 Endoplasmic reticulum stress-mediated inhibition of NSMase2 elevates plasma membrane cholesterol and attenuates NO production in endothelial cells. Biochimica et biophysica acta 18 22063270
2020 The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice. BMC medicine 17 33208172
2017 Involvement of Cryptosporidium parvum Cdg7_FLc_1000 RNA in the Attenuation of Intestinal Epithelial Cell Migration via Trans-Suppression of Host Cell SMPD3. The Journal of infectious diseases 17 28961856
2022 Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice. Pharmaceutics 16 36297501
2014 Effect of procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3. Journal of lipid research 16 25047167
2024 A blood glucose fluctuation-responsive delivery system promotes bone regeneration and the repair function of Smpd3-reprogrammed BMSC-derived exosomes. International journal of oral science 15 39616150
2016 ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation. Journal of lipid research 15 27013100
2023 Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR-/- mice. Scientific reports 14 36894641
2019 Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization. The American journal of pathology 12 31199918
2016 The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures. Calcified tissue international 12 27444010
2015 The hyaluronic acid inhibitor 4-methylumbelliferone is an NSMase2 activator-role of Ceramide in MU anti-tumor activity. Biochimica et biophysica acta 11 26548718
2022 Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation. International journal of molecular sciences 9 36430407
2024 Dynamic changes in the proximitome of neutral sphingomyelinase-2 (nSMase2) in TNFα stimulated Jurkat cells. Frontiers in immunology 8 39044828
2023 Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice. Pharmaceutics 8 37765332
2025 Genistein alleviates rheumatoid arthritis by inhibiting fibroblast-like synovial exosome secretion regulated by the Rab27/nSMase2/Mfge8 pathway. Food & function 7 39895262
2022 Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy. International journal of molecular sciences 7 35163475
2014 Hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by oxidized LDL. Redox biology 7 25555205
2025 Role of Acorus calamus extract in reducing exosome secretion by targeting Rab27a and nSMase2: a therapeutic approach for breast cancer. Molecular biology reports 4 39812915
2014 Inducible transient expression of Smpd3 prevents early lethality in fro/fro mice. Genesis (New York, N.Y. : 2000) 4 24585429
2025 SMPD3 as a Potential Biomarker and Therapeutic Target in Hepatocellular Carcinoma. International journal of genomics 3 40226357
2025 SMPD3 Inhibition Contributes to Nicotinamide-Ameliorated Hepatic Steatosis in Chronic Alcohol-Fed Mice. Journal of agricultural and food chemistry 3 40404566
2024 Challenging the conventional wisdom: Re-evaluating Smpd3's role in extracellular vesicle biogenesis. Journal of extracellular biology 3 39525277
2012 Evidence for coordination of lysosomal (ASMase) and plasma membrane (NSMase2) forms of sphingomyelinase from mutant mice. FEBS letters 3 23046545
2024 Transcriptomics analysis reveals potential regulatory role of nSMase2 (Smpd3) in nervous system development and function of middle-aged mouse brains. Genes, brain, and behavior 2 39171374
2024 Exploring the Role of SMPD3 in the lncRNA-miRNA-mRNA Regulatory Network in TBI Progression by Influencing Energy Metabolism. Journal of inflammation research 2 39677286
2025 Smpd3 regulates odontoblast differentiation through the Shh-Gli1 pathway. Bone 1 40639673
2025 Glucocorticoids regulate small extracellular vesicle (sEV) release via activation of nSMase2. bioRxiv : the preprint server for biology 1 41279432
2024 nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer. bioRxiv : the preprint server for biology 1 39399775
2023 Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer's disease. Research square 1 37502930
2023 SMPD3 expression is spatially regulated in the developing embryo by SOXE factors. Developmental biology 1 38052296
2026 Glucocorticoids regulate small extracellular vesicle release via activation of nSMase2. Journal of cell science 0 42059363
2024 Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs. Pharmaceutics 0 39861669

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