Affinage

SMPD3

Sphingomyelin phosphodiesterase 3 · UniProt Q9NY59

Length
655 aa
Mass
71.1 kDa
Annotated
2026-04-28
61 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMPD3 (nSMase2) is a Mg²⁺-dependent neutral sphingomyelinase that hydrolyzes sphingomyelin to ceramide and phosphocholine, functioning as a central regulator of ceramide-dependent membrane remodeling in the Golgi secretory pathway, extracellular vesicle biogenesis, and cell-fate decisions across skeletal, neural, and vascular tissues. Its catalytic domain adopts a DNase-I-type fold regulated by an allosteric 'DK switch' that is activated upon phosphatidylserine binding by the N-terminal membrane-anchoring domain; post-translational control involves p38 MAPK- and PKCδ-mediated translocation from the Golgi to the plasma membrane and serine phosphorylation tonically suppressed by calcineurin (PP2B), which is relieved under oxidative stress (PMID:28652336, PMID:17085432, PMID:18653803, PMID:20106976). In the Golgi, SMPD3 maintains the sphingomyelin–ceramide–diacylglycerol cycle essential for vesicle budding and protein secretion; its loss in chondrocytes, hypothalamic neurons, and cortical neurons causes dysproteostasis, ER stress, and impaired extracellular matrix or neuropeptide secretion, manifesting as chondrodysplasia, dwarfism, combined pituitary hormone deficiency, and progressive neurodegeneration with APP/Aβ/pTau accumulation (PMID:15764706, PMID:27882938, PMID:29725009, PMID:31199918). At the plasma membrane, nSMase2-generated ceramide drives ESCRT-independent exosome/small extracellular vesicle formation, enabling intercellular transfer of miRNAs and pathological tau seeds; pharmacological inhibition reduces tau propagation in vivo and attenuates atherosclerosis through Nrf2-dependent anti-inflammatory mechanisms (PMID:23439645, PMID:38049923, PMID:29794115).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 Medium

    Establishing that nSMase2 localizes to the plasma membrane and elevates intracellular ceramide with downstream signaling consequences answered whether SMPD3 encodes a functionally active sphingomyelinase capable of modulating inflammatory kinase cascades.

    Evidence Adenoviral expression in primary rat hepatocytes with ceramide quantification and JNK phosphorylation assays

    PMID:15059969

    Open questions at the time
    • PP2A linkage defined pharmacologically only, not by genetic manipulation
    • Endogenous expression and activity levels in hepatocytes not established
  2. 2005 High

    Genetic ablation of Smpd3 in mice revealed it is the sole neutral sphingomyelinase in hypothalamic Golgi membranes and is indispensable for pituitary hormone secretion and skeletal development, establishing non-redundant in vivo functions.

    Evidence Smpd3 knockout and positional cloning of fragilitas ossium mutation in mice, enzymatic activity assays, subcellular fractionation, skeletal phenotyping

    PMID:15764706 PMID:16025116

    Open questions at the time
    • Human genetic disease counterpart not yet identified from these studies
    • Whether bone phenotype reflects Golgi secretory defect vs. direct mineralization role was unresolved
  3. 2006 High

    Demonstrating that TNFα triggers p38 MAPK-dependent translocation of nSMase2 from Golgi to plasma membrane defined the first regulated trafficking mechanism controlling enzyme compartmentalization and downstream adhesion molecule induction.

    Evidence siRNA, overexpression, p38 MAPK inhibition, subcellular fractionation in A549 lung epithelial cells

    PMID:17085432

    Open questions at the time
    • Direct phosphorylation sites on nSMase2 mediating translocation not mapped
    • Whether translocation per se or enzymatic activation at PM drives VCAM/ICAM unclear
  4. 2008 High

    Identification of PKCδ as an independent mediator of nSMase2 Golgi-to-PM translocation, and detection of SMPD3 mutations in human leukemias, expanded the regulatory network and implicated SMPD3 loss in ceramide-mediated apoptosis evasion.

    Evidence PKC isoform-specific siRNA and inhibitors in lung epithelial cells; genomic sequencing of AML/ALL samples with functional reconstitution in SMPD3-null tumor cells

    PMID:18299447 PMID:18653803

    Open questions at the time
    • PKCδ phosphorylation site(s) on nSMase2 not identified
    • Leukemia mutations are correlative; causality in human disease not established
  5. 2009 Medium

    Showing that Runx2 directly binds the Smpd3 promoter downstream of BMP2 signaling established the first transcription factor directly activating SMPD3 in osteoblast differentiation.

    Evidence BMP2 treatment, Runx2 transfection, EMSA, promoter-reporter assays in osteoblastic cells

    PMID:19250608

    Open questions at the time
    • ChIP-seq confirmation of Runx2 occupancy in vivo not performed
    • Contribution relative to other transcriptional inputs unclear
  6. 2010 High

    Discovery that calcineurin (PP2B) directly binds nSMase2 and tonically suppresses its serine phosphorylation/activity resolved how oxidative stress activates the enzyme: calcineurin inhibition releases this brake.

    Evidence Co-immunoprecipitation of calcineurin–nSMase2, calcineurin-binding-site mutagenesis, phosphorylation and activity assays under oxidative stress

    PMID:20106976

    Open questions at the time
    • Specific serine residue(s) dephosphorylated by calcineurin not mapped
    • In vivo relevance of calcineurin–nSMase2 axis not tested
  7. 2011 High

    Isoform-selective comparison established nSMase2 as the primary TNFα-responsive neutral sphingomyelinase controlling cellular ceramide levels, and separate work showed nSMase2 loss causes G1/G0 cell-cycle arrest, linking ceramide homeostasis to cell proliferation.

    Evidence Isoform-specific siRNA/overexpression with sphingolipid MS in MCF-7 cells; fro/fro fibroblast cell-cycle analysis with Smpd3 gene rescue

    PMID:21303347 PMID:23046545

    Open questions at the time
    • Cell-cycle arrest mechanism downstream of ceramide not resolved
    • Whether nSMase1/3 compensate in other tissues unknown
  8. 2013 High

    Demonstration that nSMase2 controls exosomal miRNA secretion and horizontal transfer to endothelial cells established a new biological axis — ceramide-dependent extracellular vesicle biogenesis — with consequences for angiogenesis and metastasis.

    Evidence nSMase2 knockdown/GW4869 inhibition, exosome isolation and miRNA profiling, miR-210 transfer assays, in vivo tumor metastasis models

    PMID:23439645

    Open questions at the time
    • Mechanism of miRNA sorting into ceramide-enriched EV membranes unclear
    • Relative contribution of ESCRT-dependent vs. nSMase2-dependent EV pathways not quantified
  9. 2016 High

    Conditional knockout studies dissected tissue-autonomous roles: chondrocyte-specific deletion recapitulated cartilage but not bone defects while osteoblast deletion was additionally required, and Golgi lipidomics revealed that SMPD3 loss disrupts the SM–ceramide–DAG cycle causing ER stress and dysproteostasis.

    Evidence Col2a1-Cre and Osx-Cre conditional KO mice, lipidomic analysis, UPR markers, SOX9 transcriptional suppression, promoter analysis

    PMID:27325675 PMID:27882938

    Open questions at the time
    • How ceramide vs. DAG depletion individually contributes to vesicle budding defect not resolved
    • SOX9 binding site in SMPD3 promoter not mapped by ChIP
  10. 2017 High

    The 1.85-Å crystal structure of the nSMase2 catalytic domain revealed a DNase-I fold with a conserved 'DK switch' gating the active site, and demonstrated that the N-terminal domain allosterically activates catalysis via phosphatidylserine binding, providing the first structural framework for enzyme regulation and inhibitor design.

    Evidence X-ray crystallography, site-directed mutagenesis of DK switch, in vitro enzymatic and lipid-binding assays

    PMID:28652336

    Open questions at the time
    • Full-length structure including transmembrane/NTD not solved
    • Structural basis for GW4869 inhibition inferred but not co-crystallized
  11. 2018 High

    Two parallel advances showed nSMase2 operates at the nexus of neurodegeneration and vascular disease: neuronal Golgi SMPD3 loss causes APP/Aβ/pTau accumulation with cognitive decline, while nSMase2 inhibition reduces atherosclerosis via Nrf2 activation, and cambinol targeting the DK switch suppresses EV-mediated tau propagation.

    Evidence Smpd3−/− mouse brain immunohistochemistry/behavior; Apoe−/−;Smpd3 mutant and GW4869-treated mice with Nrf2 epistasis; cambinol dose-response enzyme assay, EV quantification, tau seeding assay, oral dosing PK

    PMID:29604274 PMID:29725009 PMID:29794115

    Open questions at the time
    • Whether neuronal phenotype is purely Golgi-based or also involves PM ceramide generation unresolved
    • Cambinol selectivity for nSMase2 vs. other targets not fully characterized
  12. 2019 Medium

    Extension to infectious disease and fracture healing: nSMase2 is required for exosomal packaging and intercellular transmission of ZIKV in cortical neurons, and conditional osteoblast/chondrocyte KO impairs fracture healing via Shh-independent mechanisms, refining tissue-specific roles.

    Evidence SMPD3 siRNA and GW4869 in primary cortical neurons with viral load/exosome quantification; Smpd3flox/flox;Osx-Cre fracture model; micro-CT and DXA of fro/fro mice clarifying mineralization phenotype

    PMID:30530524 PMID:30866785 PMID:31199918

    Open questions at the time
    • How nSMase2 selectively packages viral RNA into exosomes mechanistically unclear
    • Whether fro/fro mineralization phenotype depends on genetic background not settled
  13. 2023 High

    Pharmacological nSMase2 inhibition with PDDC in tauopathy models normalized brain ceramides, reduced pTau propagation to contralateral hippocampus, and lowered pTau in plasma neuronal EVs, validating nSMase2 as a druggable node in tau spreading, while SOX9/SOX10 were identified as direct transcriptional activators of SMPD3 in neural crest via an intronic enhancer.

    Evidence PS19 and AAV-tau seeding mouse models with oral PDDC, ceramide lipidomics, plasma EV pTau ELISA; ChIP-seq and enhancer-reporter mutagenesis in Xenopus/chick neural crest

    PMID:38049923 PMID:38052296

    Open questions at the time
    • Long-term safety and blood-brain barrier pharmacology of PDDC need further evaluation
    • Whether SOX9/SOX10 enhancer is active in adult neurons or only embryonic neural crest unknown
  14. 2024 Medium

    APEX2 proximity labeling revealed that TNFα triggers rapid enzymatic-activity-dependent remodeling of the nSMase2 plasma-membrane interactome, enriching vesicle transport, recycling endosome, and TGN proteins within minutes.

    Evidence APEX2-nSMase2 fusion in Jurkat cells, quantitative MS, comparison of active vs. catalytically dead mutant after TNFα stimulation

    PMID:39044828

    Open questions at the time
    • Individual proximal partners not validated by orthogonal methods
    • Whether interactome remodeling is ceramide-dependent or protein-conformational unknown
  15. 2025 Medium

    nSMase2 was placed downstream of Top2B/p53 in doxorubicin cardiotoxicity driving cardiomyocyte senescence (not death), and separately shown to mediate glucocorticoid-induced sEV secretion via mitochondrial ROS/mPTP activation, broadening the upstream signals converging on the enzyme.

    Evidence fro/fro mice in chronic doxorubicin model with echocardiography and DUSP4 identification (preprint); TIRF live imaging of sEV release with GW4869, Rab27a KD, ROS scavengers in neurons (preprint)

    PMID:41279432 PMID:bio_10.1101_2025.03.20.644150

    Open questions at the time
    • Both findings await peer review
    • DUSP4 as a direct transcriptional target of nSMase2-generated ceramide requires validation
    • Whether mPTP-nSMase2 axis operates outside glucocorticoid signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of nSMase2 with its transmembrane domain, the identity of specific serine phosphorylation sites controlling activity, the mechanism by which ceramide selectively sorts cargo into exosomes, and whether SMPD3 mutations cause a defined human Mendelian skeletal or neurological disorder.
  • Full-length structure including NTD/membrane domain not solved
  • Phosphorylation sites mediating calcineurin and p38 MAPK regulation not mapped
  • Mechanism of selective miRNA/protein cargo sorting into ceramide-enriched EVs unknown
  • No confirmed human Mendelian disease caused by SMPD3 loss-of-function

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0008289 lipid binding 1
Localization
GO:0005794 Golgi apparatus 5 GO:0005886 plasma membrane 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-5357801 Programmed Cell Death 2
Partners
EEDMAPK14PPP3CAPRKCДRACK1RUNX2SOX10SOX9

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 at 1.85-Å resolution reveals a DNase-I-type fold with a hydrophobic track to the active site blocked by an evolutionarily conserved 'DK switch' motif. The N-terminal domain (NTD) binds phosphatidylserine and serves as both a membrane anchor and allosteric activator of the C-terminal catalytic domain via the juxtamembrane region. Mutation of the universally conserved Asp residue in the DK switch disrupts catalysis, allosteric activation, phosphatidylserine stimulation, and GW4869 inhibition. Crystal structure (1.85 Å), in vitro enzymatic assay, site-directed mutagenesis, lipid-binding assays Proceedings of the National Academy of Sciences of the United States of America High 28652336
2005 SMPD3 (nSMase2) is the neutral sphingomyelinase activity present in the Golgi membranes of hypothalamic neurosecretory neurons; its genetic deletion in mice eliminates neutral sphingomyelinase activity and causes dwarfism and combined pituitary hormone deficiency, demonstrating an essential role in the hypothalamus-pituitary secretory pathway. Smpd3 knockout mouse generation, enzymatic activity assay, subcellular fractionation into detergent-resistant Golgi subdomains, phenotypic characterization Proceedings of the National Academy of Sciences of the United States of America High 15764706
2005 A deletion in Smpd3 that eliminates enzymatic activity causes osteogenesis and dentinogenesis imperfecta in mice (fragilitas ossium mutation), establishing SMPD3 as required for normal bone and dentin mineralization. Positional cloning, enzymatic activity assay of mutant tissue, skeletal phenotypic analysis Nature genetics High 16025116
2016 SMPD3 deficiency in the Golgi compartment of chondrocytes and hypothalamic neurons disrupts homeostasis of the sphingomyelin–ceramide–diacylglycerol (Golgi SMPD3-SMS1) cycle, impairing membrane remodeling required for vesicle formation, causing dysproteostasis, unfolded protein response, ER stress, and arrest of extracellular matrix protein secretion. Smpd3-/- mouse model, lipidomic analysis, immunohistochemistry, UPR/ER stress markers, primary chondrocyte cultures Cell death & disease High 27882938
2006 In TNF-α-stimulated lung epithelial cells (A549), nSMase2 translocates acutely to the plasma membrane in a time- and dose-dependent manner; this translocation and the resulting increase in N-SMase activity are regulated upstream by p38-alpha MAPK but not ERK or JNK. nSMase2 activation is required for TNF-α-induced upregulation of VCAM-1 and ICAM-1 largely independent of NF-κB. Overexpression, siRNA knockdown, pharmacological inhibitors, p38 MAPK inhibition, subcellular fractionation, in vitro N-SMase activity assay, immunofluorescence The Journal of biological chemistry High 17085432
2008 PKC-delta mediates TNF-α- and PMA-induced translocation of nSMase2 from the Golgi to the plasma membrane in lung epithelial cells, acting independently of p38 MAPK and independently of nSMase2 enzymatic activity regulation. PKC-delta knockdown inhibits downstream VCAM and ICAM induction. Pharmacological PKC inhibitors, specific siRNA for PKC isoforms, immunofluorescence localization, co-immunoprecipitation, in vitro N-SMase activity assay Molecular pharmacology High 18653803
2010 nSMase2 is a serine-phosphoprotein; the phosphatase calcineurin (PP2B) binds directly to nSMase2 and acts as an on/off switch for its phosphorylation and activity. Under oxidative stress, calcineurin is inhibited/degraded, releasing nSMase2 from its control, increasing phosphorylation and enzymatic activity. A calcineurin-binding-site mutant of nSMase2 shows constitutively elevated phosphorylation and activity that no longer responds to oxidative stress. Direct co-immunoprecipitation of calcineurin with nSMase2, phosphorylation assays (serine-specific), site-directed mutagenesis of CaN-binding site, in vitro N-SMase activity assay, PMA/anisomycin treatment The Journal of biological chemistry High 20106976
2013 nSMase2 regulates exosomal microRNA secretion from cancer cells; nSMase2-dependent exosomal miR-210 is transferred horizontally to endothelial cells, suppresses target gene expression, and promotes angiogenesis and tumor metastasis. nSMase2 knockdown/inhibition (GW4869), exosome isolation and miRNA profiling, miR-210 transfection into endothelial cells, in vivo tumor metastasis assays The Journal of biological chemistry High 23439645
2004 Adenovirus-mediated expression of NSMase-2 in primary rat hepatocytes increases intracellular ceramide levels and localizes to the plasma membrane. NSMase-2 expression amplifies IL-1β-induced JNK phosphorylation; this potentiation is mediated by a PP2A-family phosphatase, potentially through modulation of IRAK phosphorylation. Adenoviral gene transfer, immunofluorescence localization, ceramide measurement, kinase activity assay (JNK phosphorylation), pharmacological PP2A inhibitors FASEB journal Medium 15059969
2011 In MCF-7 cells, TNF-α activates nSMase2 (but not nSMase1 or nSMase3) as the primary N-SMase isoform through post-transcriptional mechanisms; only nSMase2 overexpression significantly increases cellular ceramide and decreases sphingomyelin, while nSMase3 overexpression has no effect on in vitro N-SMase activity or cellular sphingolipids. Isoform-specific siRNA knockdown, tagged and untagged overexpression of nSMase1/2/3, in vitro N-SMase activity assay, sphingolipid mass measurement by mass spectrometry The Biochemical journal High 21303347
2008 SMPD3 mutations found in human acute myeloid and acute lymphoid leukemias cause defects in protein stability and localization; reconstitution of SMPD3 expression in mouse tumor cells lacking the gene enhanced TNF-induced reduction of cell viability, placing SMPD3 in the ceramide-mediated apoptosis pathway. Genomic deletion mapping, nucleotide sequencing of human cancer samples, functional reconstitution in SMPD3-null tumor cells, cell viability assay Blood Medium 18299447
2016 Smpd3 expression in both chondrocytes (via Col2a1-Cre) and osteoblasts (via Osx-Cre) is required for normal endochondral bone development; chondrocyte-specific KO recapitulates cartilage but not bone phenotype of fro/fro mice, while combined chondrocyte+osteoblast KO mimics full fro/fro skeletal phenotype. PTHrP suppresses Smpd3 expression through transcription factor SOX9. Conditional Cre-loxP knockout mice, transgenic rescue in fro/fro mice, RT-PCR/promoter analysis, skeletal phenotyping Molecular and cellular biology High 27325675
2016 All-trans retinoic acid (ATRA) transcriptionally induces nSMase2 via retinoic acid receptor-α through direct modulation of histone acetylation; the histone acetyltransferases CBP/p300 are required for ATRA induction, and HDAC4/5 are negative regulators of nSMase2 expression. Retinoic acid receptor siRNA, HDAC inhibitor (TSA) treatment, ChIP for histone acetylation marks, CBP/p300 knockdown, promoter-reporter assays Journal of lipid research Medium 27013100
2009 BMP2 stimulation induces Smpd3 expression, and the Runx2 transcription factor directly binds the Smpd3 promoter at Runx2-responsive elements (RRE) at -562 to -557 and -355 to -350 bp to activate transcription. BMP2 treatment, Runx2 transfection, promoter-reporter assays, electrophoretic mobility shift assay (EMSA) BMB reports Medium 19250608
2013 In cerebral ischemia, nSMase2 activity is induced in astrocytes (not neurons) via A2B adenosine receptor → p38MAPK signaling (not via TNF-α receptor/RACK1/EED); nSMase2 activation drives ceramide accumulation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6) mediating neuronal damage. Immunoprecipitation confirmed enhanced binding of nSMase2 with RACK1 and EED after ischemia. Four-vessel occlusion ischemia model, SMase activity assay, co-immunoprecipitation (nSMase2 with RACK1 and EED), pharmacological inhibitors, immunohistochemistry, cytokine RT-PCR, GW4869 inhibition Journal of neuroinflammation Medium 24007266
2018 SMPD3 deficiency in the neuronal Golgi compartment inhibits vesicular protein transport, causing accumulation of APP, Aβ, and phosphorylated Tau, unfolded protein response, and apoptosis, leading to progressive cognitive impairment in smpd3-/- mice. Smpd3-/- mouse model, immunohistochemistry, protein aggregation assays, behavioral testing, lipidomics of Golgi fraction Cell death & disease High 29725009
2018 nSMase2 inhibition with cambinol (which targets the DK switch active-site motif) reduces in vitro ceramide production in dose-response, suppresses extracellular vesicle production, and reduces tau seed propagation between cells; oral administration reduces brain nSMase2 activity in vivo. In vitro nSMase2 enzymatic assay, EV quantification, tau propagation cell assay, molecular docking to DK switch, oral dosing in mice Biochemical and biophysical research communications Medium 29604274
2019 ZIKV infection induces both activity and gene expression of nSMase2/SMPD3 in cortical neurons; nSMase2 activity is required for packaging of ZIKV RNA and protein into exosomes and for intercellular viral transmission. Silencing SMPD3 or treatment with GW4869 reduces viral burden and exosomal ZIKV transmission. Primary murine cortical neuron culture, siRNA silencing of SMPD3, GW4869 pharmacological inhibition, cryo-electron microscopy of neuronal exosomes, viral load quantification, RNaseA and neutralizing antibody treatment Emerging microbes & infections Medium 30866785
2019 SMPD3/nSMase2 deficiency in fro/fro mice causes chondrodysplasia through disruption of the Golgi secretory pathway in chondrocytes of the epiphyseal growth zone, but shows unimpaired skeletal mineralization, distinguishing SMPD3's role in Golgi-dependent proteostasis from direct mineralization control. Smpd3-/- mouse model, peripheral quantitative CT, high-resolution micro-CT, dual-energy X-ray absorptiometry, immunohistochemistry, biochemical analyses The American journal of pathology High 31199918
2019 BMP-2 positively regulates Smpd3 expression in chondrocytes via p38 MAPK; PTHrP negatively regulates Smpd3 expression, opposing BMP-2. SMPD3 deficiency in osteoblasts/late-stage chondrocytes impairs chondrocyte apoptosis and ECM mineralization during fracture healing. Conditional Smpd3 KO (Smpd3flox/flox;Osx-Cre), fracture healing model, RT-PCR, p38 MAPK inhibitors, ATDC5 chondrogenic cell culture Molecular and cellular biology Medium 30530524
2011 ER stress inhibits NSMase2 activity in endothelial cells, leading to elevation of plasma membrane cholesterol and attenuation of eNOS phosphorylation and NO production; NSMase2 knockdown recapitulates these effects while NSMase2 overexpression in ER-stressed cells restores cholesterol levels and partially rescues NO production. NSMase2 overexpression and siRNA knockdown in BAEC, cholesterol measurement (epifluorescence and cholesterol oxidase), eNOS phosphorylation assay, NO measurement, ER stress induction with tunicamycin and palmitate Biochimica et biophysica acta Medium 22063270
2018 nSMase2 deficiency or GW4869 inhibition reduces atherosclerotic lesions in Apoe-/- mice; the anti-inflammatory mechanism involves Nrf2 pathway activation in endothelial cells and macrophages, as GW4869 protection is abolished by Nrf2 siRNA knockdown or in Nrf2-KO macrophages. Apoe-/-;Smpd3 mutant mice, GW4869 pharmacological inhibition, Nrf2 siRNA knockdown, Nrf2-KO macrophages, lesion quantification, inflammatory gene expression Arteriosclerosis, thrombosis, and vascular biology High 29794115
2017 TLR signaling induces abnormal expression of SMPD3 and causes its translocation from the Golgi apparatus in B cells and macrophages; SMPD3 dysfunction enhances TLR-induced inflammatory responses in turn. TLR stimulation of B cells and macrophages from SLE patients and lupus-prone mice, immunofluorescence localization, gene expression analysis Scandinavian journal of immunology Low 28889482
2023 Human tau expression in PS19 transgenic mice elevates brain ceramides and nSMase2 activity; pharmacological inhibition of nSMase2 with PDDC normalizes ceramide levels, reduces pTau propagation to contralateral hippocampus in an AAV tau seeding model, and reduces pTau content in neuronal-derived plasma EVs. PS19 transgenic mouse model, AAV unilateral tau seeding propagation model, nSMase2 activity assay, ceramide lipidomics, plasma EV isolation and pTau ELISA, oral PDDC dosing with PK/PD measurements Translational neurodegeneration High 38049923
2022 α2,6-Sialylation by ST6Gal-I regulates nSMase2 activity; reduced α2,6-sialylation impairs nSMase2 activity and nSMase2-dependent sorting of specific miRNAs (including miR-100-5p) into exosomes, which promotes HCC cell migration and invasion via the PI3K/AKT pathway. ST6Gal-I knockdown, miRNA exosomal profiling, nSMase2 activity assay, cell migration and invasion assays Journal of physiology and biochemistry Medium 35984620
2023 SOXE-family transcription factors SOX9 and SOX10 directly regulate SMPD3 expression in migrating neural crest cells through enhancer sequences in the first intron of the SMPD3 locus; ChIP-seq and nascent transcription analysis show SOX10 directly binds an SMPD3 enhancer specific to migratory neural crest. Enhancer reporter assays, site-directed mutation of putative TF binding sites, SOX9/SOX10 knockdown, ChIP-seq, nascent transcription analysis in Xenopus/chick neural crest Developmental biology Medium 38052296
2017 Cryptosporidium parvum RNA (Cdg7_FLc_1000) delivered into intestinal epithelial cells suppresses SMPD3 expression through histone methyltransferase G9a-mediated H3K9 methylation at the SMPD3 locus; the DNA-binding repressor PRDM1 is required for assembly of the RNA into the G9a complex and enrichment of H3K9 methylation at SMPD3, resulting in inhibited epithelial cell migration. In vitro/in vivo intestinal cryptosporidiosis models, siRNA KD of G9a/PRDM1, ChIP for H3K9me2 at SMPD3 locus, cell migration assay The Journal of infectious diseases Medium 28961856
2024 Proximity labeling (APEX2) of nSMase2 in Jurkat cells reveals that TNF-α stimulation within 5 min induces significant dynamic remodeling of the nSMase2 plasma-membrane proximal protein network, including enrichment of proteins related to vesicle-mediated transport, recycling endosomes, trans-Golgi network, and exocytic vesicles; recruitment of most proteins depends on nSMase2 enzymatic activity. APEX2 proximity labeling fused to nSMase2, streptavidin affinity purification, quantitative mass spectrometry, TNF-α stimulation time course, comparison of enzymatically active vs. inactive nSMase2 Frontiers in immunology Medium 39044828
2025 Glucocorticoids stimulate sEV/exosome secretion in neurons via nSMase2 activation; this process requires Rab27a and is downstream of GC-induced mitochondrial reactive oxygen species production and mitochondrial permeability transition pore (mPTP) opening, which activates nSMase2 to drive ceramide-dependent sEV formation. TIRF microscopy with mCh-CD63-pHluorin reporter for live sEV release visualization, Rab27a KD, nSMase2 inhibition (GW4869), mPTP inhibitors, ROS scavengers bioRxivpreprint Medium 41279432
2025 nSMase2 induction by doxorubicin in cardiomyocytes is downstream of Top2B and p53; nSMase2 is required for doxorubicin-induced cardiomyocyte senescence (but not cell death) both in vitro and in vivo. fro/fro (nSMase2-null) mice are protected from chronic doxorubicin-induced cardiac damage. DUSP4 is identified as a downstream transcriptional target of nSMase2 in doxorubicin-treated cardiomyocytes. Chronic doxorubicin mouse model in fro/fro vs. WT mice, echocardiography, Top2B/p53 upstream pathway analysis, senescence assays in vitro and in vivo, microarray for downstream targets, DUSP4 identification bioRxivpreprint Medium bio_10.1101_2025.03.20.644150
2025 Smpd3 regulates odontoblast differentiation through the Shh-Gli1 signaling pathway; Smpd3 knockdown impairs differentiation and mineralization while overexpression enhances dentinogenic markers (Dspp, Dmp1) in a Shh-dependent manner. siRNA knockdown and overexpression in mouse dental papilla cells (mDPCs), bulk RNA-seq, tooth germ culture ex vivo, Shh pathway activity assays Bone Medium 40639673
2012 NSMase2 (fro/fro) and ASMase serve two distinct subcellular pathways for sphingomyelin catabolism with distinct functions; NSMase2 deficiency causes G1/G0 cell cycle arrest correctable by Smpd3 gene transfection, while ASMase activity is substantially elevated in fro/fro fibroblasts as a compensatory response, but not vice versa. fro/fro and ASMase-/- mutant fibroblast comparison, cell cycle analysis, SMase activity assays, Smpd3 gene transfection rescue FEBS letters Medium 23046545

Source papers

Stage 0 corpus · 61 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 627 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 236 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 139 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 104 30866785
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
2018 nSMase2 (Type 2-Neutral Sphingomyelinase) Deficiency or Inhibition by GW4869 Reduces Inflammation and Atherosclerosis in Apoe-/- Mice. Arteriosclerosis, thrombosis, and vascular biology 92 29794115
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 90 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 67 24007266
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
2006 Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochimica et biophysica acta 64 16938269
2010 Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B). The Journal of biological chemistry 55 20106976
2021 Nipping disease in the bud: nSMase2 inhibitors as therapeutics in extracellular vesicle-mediated diseases. Drug discovery today 49 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 47 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 36 27882938
2024 Sedanolide alleviates DSS-induced colitis by modulating the intestinal FXR-SMPD3 pathway in mice. Journal of advanced research 30 38582300
2016 Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development. Molecular and cellular biology 29 27325675
2018 Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2. Biochemical and biophysical research communications 28 29604274
2021 Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model. Molecular brain 26 33875010
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
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
2019 Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression. Molecular and cellular biology 17 30530524
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
2016 ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation. Journal of lipid research 15 27013100
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 13 39616150
2023 Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR-/- mice. Scientific reports 13 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
2023 Microglial-Targeted nSMase2 Inhibitor Fails to Reduce Tau Propagation in PS19 Mice. Pharmaceutics 8 37765332
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 8 36430407
2024 Dynamic changes in the proximitome of neutral sphingomyelinase-2 (nSMase2) in TNFα stimulated Jurkat cells. Frontiers in immunology 7 39044828
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 Genistein alleviates rheumatoid arthritis by inhibiting fibroblast-like synovial exosome secretion regulated by the Rab27/nSMase2/Mfge8 pathway. Food & function 6 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 6 35163475
2014 Inducible transient expression of Smpd3 prevents early lethality in fro/fro mice. Genesis (New York, N.Y. : 2000) 4 24585429
2025 Role of Acorus calamus extract in reducing exosome secretion by targeting Rab27a and nSMase2: a therapeutic approach for breast cancer. Molecular biology reports 3 39812915
2025 SMPD3 as a Potential Biomarker and Therapeutic Target in Hepatocellular Carcinoma. International journal of genomics 3 40226357
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
2025 SMPD3 Inhibition Contributes to Nicotinamide-Ameliorated Hepatic Steatosis in Chronic Alcohol-Fed Mice. Journal of agricultural and food chemistry 0 40404566
2024 Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs. Pharmaceutics 0 39861669