Affinage

CD38

ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 · UniProt P28907

Length
300 aa
Mass
34.3 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD38 is a multifunctional type II transmembrane glycoprotein that acts both as a bifunctional ectoenzyme and as a lineage-specific signaling receptor, coupling NAD(P)+ metabolism to calcium signaling, immune activation, and tissue NAD+ homeostasis (PMID:8903511, PMID:11895784, PMID:33199924). Enzymatically, CD38 catalyzes the synthesis and hydrolysis of the Ca2+-mobilizing second messenger cyclic ADP-ribose, acting independently of inositol trisphosphate, and also degrades extracellular NAD+ to nicotinamide and ADP-ribose via its NAD+-glycohydrolase activity (PMID:8903511, PMID:7875731, PMID:11683883). A topological feature underlies its second-messenger function: CD38 occupies two opposing membrane orientations, and the type III orientation (catalytic domain facing the cytosol) drives intracellular cADPR accumulation and Ca2+ signaling (PMID:22969159). For NAADP, in vivo CD38 functions chiefly as a degrading rather than synthesizing enzyme, and NAADP production is controlled by compartmentalization: clathrin-dependent internalization delivers CD38 to the endolysosome where substrate access raises NAADP levels (PMID:22020217, PMID:29632067). As a receptor, CD38 signals through co-association with professional signaling molecules—physically associating with CD16 (FcγRIIIA) in NK cells to drive ZAP-70/MAPK phosphorylation, Ca2+ flux, and cytokine secretion, and binding CD31 (PECAM-1) to mediate leukocyte adhesion (PMID:11895784, PMID:11137554). CD38 is recruited to the immunological synapse in an antigen- and Lck-dependent manner from both plasma-membrane and recycling-endosome pools, modulating PKCθ activation and IL-2/IFN-γ production (PMID:18212246). Across multiple tissues, CD38-mediated NAD+ depletion is a central driver of pathology: its NADase activity arrests prostate cancer cell metabolism, inflammatory macrophages upregulate CD38 to lower tissue NAD+ during aging, and CD38 loss is protective in cardiac hypertrophy, lung fibrosis, osteoarthritis, and ovarian reserve depletion via NAD+- and SIRT-dependent mechanisms (PMID:30076241, PMID:33199924, PMID:28296029, PMID:35687485, PMID:36103412, PMID:37822499). Catalytic-mutant controls establish that NADase activity, not receptor function, underlies these metabolic effects (PMID:30076241, PMID:30258629). Structurally characterized epitopes on the catalytic domain underpin therapeutic anti-CD38 antibodies that act by cell depletion, cyclase/ecto-enzyme inhibition that boosts NAD+ and sirtuin activity, or dynamin-dependent CD38 internalization (PMID:27251573, PMID:35867844, PMID:37379657, PMID:30288349).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1994 Medium

    Established that CD38 receptor ligation transduces signals through a non-canonical pathway, distinguishing it from classical PLC-coupled receptors.

    Evidence Calcium flux, inositol phosphate, and tyrosine phosphorylation assays in murine B cells with anti-CD38 antibody

    PMID:7875731

    Open questions at the time
    • Did not identify the kinases or co-receptors mediating the tyrosine phosphorylation
    • No direct link to a downstream functional output
  2. 1996 High

    Defined CD38 as a bifunctional ectoenzyme producing and degrading the Ca2+-mobilizing messenger cADPR, reframing it from a pure surface marker to a metabolic enzyme.

    Evidence Biochemical ectoenzyme assays and antibody-ligation/internalization studies in hematopoietic cells

    PMID:8903511

    Open questions at the time
    • Did not resolve how an ectoenzyme generates an intracellular messenger (topological paradox)
    • Receptor versus enzyme contributions not separated
  3. 1997 Medium

    Proposed resolutions to the topological paradox—cADPR transport across the membrane and NAD+-induced CD38 internalization—addressing how surface enzyme activity reaches intracellular stores.

    Evidence Biochemical fractionation and NAD+-induced internalization experiments in lymphoid B cells

    PMID:9438379

    Open questions at the time
    • Two mechanisms with partial support; relative contributions unresolved
    • Transport route for extracellular cADPR not molecularly defined
  4. 2001 Medium

    Identified the receptor partners and downstream signaling required for CD38 to drive NK and leukocyte function, showing CD38 needs CD16 as a co-signaling partner and binds CD31 for adhesion.

    Evidence Genetic complementation of CD16-negative NK lines, signaling/cytokine assays, and CD38–CD31 binding/adhesion assays

    PMID:11137554 PMID:11282979

    Open questions at the time
    • Molecular nature of the CD38–CD16 physical interaction not yet shown
    • CD31 binding affinity and stoichiometry not defined
  5. 2001 Medium

    Linked CD38 surface NADase activity to expression level and internalization in monocytes, connecting enzyme function to cell differentiation state.

    Evidence HPLC NAD+ degradation product analysis, flow cytometry, RT-PCR, and differentiation experiments in human monocytes

    PMID:11683883

    Open questions at the time
    • Functional consequence of NAD+ depletion for monocyte biology not addressed
    • Mechanism of transcriptional downregulation during differentiation unknown
  6. 2002 High

    Demonstrated direct physical association of CD38 with CD16 and that CD16 is necessary and sufficient for CD38-driven NK activation, establishing the co-association model of CD38 receptor signaling.

    Evidence FRET and cocapping with functional Ca2+/phosphorylation/cytokine/cytotoxicity readouts in CD16+/- NK variants

    PMID:11895784

    Open questions at the time
    • Whether other lineages use distinct co-receptors not tested here
    • Enzyme activity contribution to NK signaling not separated from receptor function
  7. 2008 High

    Showed CD38 is recruited to the immunological synapse via Lck-dependent signals from membrane and recycling-endosome pools to amplify Ca2+ and modulate PKCθ and cytokine output in T cells.

    Evidence Confocal/live imaging of CD38-GFP, siRNA knockdown, Ca2+ flux, ELISA, and PKCθ phosphorylation in human T and B cells

    PMID:18212246

    Open questions at the time
    • Receptor that triggers CD38 redistribution not identified
    • Whether enzymatic activity is required for synapse function unresolved
  8. 2011 Medium

    Refined CD38's NAADP role, showing it acts in vivo as a NAADP-degrading rather than synthesizing enzyme, implying it limits desensitizing NAADP accumulation.

    Evidence siRNA silencing and CD38 KO mouse tissues versus in vitro enzymatic NAADP formation/degradation assays

    PMID:22020217

    Open questions at the time
    • Identity of the in vivo NAADP synthase left open
    • Reconciliation with later compartmentalized NAADP production needed
  9. 2011 Medium

    Connected CD38 expression to immune-regulatory and tumor signaling, marking highly suppressive Tregs downstream of PI3K p110δ and driving CLL proliferation/chemotaxis via ZAP-70/ERK.

    Evidence p110δ(D910A) Treg transcriptomics/suppression assays and CD38-ligation signaling/proliferation assays in CLL cells

    PMID:21390257 PMID:21765022

    Open questions at the time
    • Whether CD38 enzymatic vs receptor activity drives these phenotypes unclear
    • Direct receptor partners in CLL not defined
  10. 2012 High

    Resolved the topological paradox at the molecular level by demonstrating two opposing membrane orientations, with the type III (cytosol-facing catalytic) orientation enabling intracellular cADPR/Ca2+ signaling.

    Evidence Orientation-specific antibodies, site-directed mutagenesis of N-terminal cationic residues, and intracellular cADPR measurement in multiple cell types

    PMID:22969159

    Open questions at the time
    • Mechanism determining orientation choice during biogenesis unknown
    • Physiological proportion of type III in primary cells not quantified
  11. 2012 Medium

    Defined inflammatory regulation of CD38, with LPS inducing CD38 transcription via JAK-STAT and MMP-9 shedding releasing soluble CD38.

    Evidence RT-PCR, JAK-STAT and MMP-9 inhibitor studies, and ELISA for soluble CD38 in J774 macrophages

    PMID:23184288

    Open questions at the time
    • Function of shed soluble CD38 not established
    • STAT transcription factor identity not pinned down
  12. 2016 High

    Provided structural epitope maps of the CD38 catalytic domain and proof-of-concept that targeting it selectively kills malignant cells.

    Evidence X-ray crystallography of CD38–nanobody complexes and immunotoxin cytotoxicity against multiple myeloma cells

    PMID:27251573

    Open questions at the time
    • Structures did not address membrane orientation or full-length context
    • Enzymatic effect of epitope binding not measured
  13. 2018 High

    Established that CD38 NADase activity—not receptor signaling—drives metabolic reprogramming, depleting intracellular and extracellular NAD+ to arrest cell cycle and metabolism, using catalytic-dead mutant controls.

    Evidence CD38 overexpression with NADase-deficient mutant, NAD+ measurement, Seahorse flux, cell-cycle and AMPK assays, plus KO mouse tissue NAD+ in prostate models

    PMID:30076241 PMID:30258629

    Open questions at the time
    • Whether type II vs type III orientation governs intracellular NAD+ depletion not addressed
    • Source NAD+ pool (cytosolic vs extracellular import) for intracellular effects not fully resolved
  14. 2018 High

    Showed CD38 NAADP production is governed by subcellular localization, with clathrin/lysosome targeting—not enzyme activation—setting NAADP output.

    Evidence Nanobody-directed endocytosis, lysosome-targeted CD38 constructs, clathrin inhibition, and intracellular NAADP measurement in human cells

    PMID:29632067

    Open questions at the time
    • Physiological trigger for endogenous CD38 lysosomal trafficking not identified
    • Link between lysosomal NAADP and specific Ca2+ channels not shown here
  15. 2018 Medium

    Defined CD38 as an inducible amplifier of macrophage inflammation, required for IL-6/IL-12p40 secretion and glycolysis under classical activation.

    Evidence LPS/IFN-γ/IL-4 stimulation with siRNA and pharmacological CD38 inhibition and cytokine/glycolysis assays in primary human macrophages

    PMID:30042766

    Open questions at the time
    • Whether enzymatic NAD+ depletion mediates the cytokine effect not separated
    • Downstream metabolic node linking CD38 to glycolysis undefined
  16. 2018 Medium

    Clarified mechanisms of anti-CD38 therapeutics, showing daratumumab induces dynamin/clathrin-dependent CD38 internalization and degradation that reshapes NK/monocyte function and impairs MM adhesion to sensitize to bortezomib.

    Evidence Flow cytometry of surface CD38 after daratumumab, Dynasore rescue of adhesion, monocyte activation/phagocytosis and bortezomib combination assays in vitro and in vivo

    PMID:30288349 PMID:32296125

    Open questions at the time
    • Adapter machinery driving antibody-induced internalization not fully defined
    • Relative contribution of internalization vs effector killing in patients unclear
  17. 2017 Medium

    Implicated CD38 NAD+ depletion in cardiac disease, linking it to SIRT3 suppression and Ca2+-NFAT signaling in angiotensin II-induced hypertrophy.

    Evidence CD38 KO mice with Ang-II infusion, cardiac histology, and RNAi knockdown with signaling readouts in H9c2 cardiomyocytes

    PMID:28296029

    Open questions at the time
    • Direct demonstration that NADase activity (not receptor) drives the SIRT3 axis not shown
    • Cell type responsible (cardiomyocyte vs infiltrating cells) in vivo not isolated
  18. 2019 Medium

    Extended CD38 signaling control to B-cell receptor pathways in CLL and showed daratumumab can directly trigger FcγR-dependent apoptosis.

    Evidence Immunoblotting of Syk/BTK/PLCγ2/ERK/AKT after CD38 targeting, apoptosis and FcγR-blocking assays, and CLL xenografts

    PMID:30940652

    Open questions at the time
    • Mechanistic coupling of CD38 to the BCR module not structurally defined
    • Whether ectoenzyme activity participates not tested
  19. 2020 High

    Defined feedback and aging circuits of CD38 NADase, with a CD38–TTP–Sirt1 loop resolving sepsis inflammation and senescence-driven macrophage CD38 induction lowering tissue NAD+ during aging.

    Evidence Sepsis models with CD38/TTP KO and Sirt1 inhibition; tissue macrophage NADase activity, SASP induction, and senescent cell depletion in aged mice

    PMID:31995750 PMID:33199924

    Open questions at the time
    • Receptors/transcription factors linking SASP to CD38 induction incompletely mapped
    • Whether other NAD-consuming enzymes contribute to tissue decline not excluded
  20. 2022 Medium

    Linked CD38-driven NAD+ loss to oxidative damage and ferroptosis, with high CD38 raising ROS and causing Cys7-sulfonation-dependent DHFR degradation rescuable by NAD+ precursor.

    Evidence CD38 overexpression, ROS measurement, DHFR Cys7 mutagenesis, autophagy/proteasome inhibitors, ferroptosis assays, and NMN rescue

    PMID:36351893

    Open questions at the time
    • Direct enzymatic-mutant control for CD38 NADase in this pathway not described
    • Generality across cell types beyond macrophages unclear
  21. 2022 Medium

    Generalized CD38 NAD+ depletion as a driver of tissue fibrosis and aging, with CD38 elevation in alveolar epithelial cells promoting senescence and lung fibrosis.

    Evidence scRNA-seq, CD38 KO and pharmacological inhibition, NAD+ measurement, and bleomycin fibrosis model in mice

    PMID:35687485

    Open questions at the time
    • Catalytic-mutant proof in epithelium not provided
    • Trigger of CD38 elevation in AECs not defined
  22. 2022 Medium

    Demonstrated therapeutic enzyme inhibition without cell killing as a distinct anti-CD38 strategy, with a biparatopic Fc-silenced antibody inhibiting ecto-enzyme activity and boosting NAD+ and sirtuin activity.

    Evidence Fluorescence enzymatic assays, intracellular NAD+ and sirtuin activity measurement, SPR binding, and ADCC/CDC assays for TNB-738

    PMID:35867844

    Open questions at the time
    • In vivo NAD+ restoration efficacy not detailed here
    • Durability of enzyme inhibition not addressed
  23. 2023 High

    Combined structural epitope definition with dual therapeutic mechanism, showing a HexaBody antibody inhibits CD38 cyclase activity while Fc hexamerization potentiates complement-dependent killing.

    Evidence Co-crystallization, cyclase inhibition spectroscopy, CDC/ADCC/ADCP/apoptosis assays, and patient-derived xenografts

    PMID:37379657

    Open questions at the time
    • Whether cyclase inhibition contributes clinically beyond killing not resolved
    • Epitope effect on type III orientation not examined
  24. 2023 Medium

    Extended CD38 NAD+ consumption to reproductive aging and joint disease, with CD38 loss enlarging ovarian reserve and protecting cartilage after injury via raised NAD+.

    Evidence CD38 KO mouse ovarian phenotyping/NAD+ measurement and chondrocyte gain/loss-of-function with NAD+:NADH measurement plus DMM joint injury model

    PMID:36103412 PMID:37822499

    Open questions at the time
    • Cell-autonomous vs systemic NAD+ effects not fully separated
    • Whether receptor signaling contributes alongside NADase not addressed
  25. 2016 Medium

    Revealed a neurological requirement for CD38 in learning and memory that is independent of classical synaptic plasticity.

    Evidence Behavioral testing (water maze, fear conditioning, object recognition) and hippocampal LTP/LTD electrophysiology in CD38 KO mice

    PMID:26856703

    Open questions at the time
    • Molecular mediator (cADPR/Ca2+ vs oxytocin-related signaling) not identified here
    • Brain cell type responsible not localized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the determinants of CD38 membrane orientation and subcellular trafficking are physiologically regulated to dictate when CD38 depletes NAD+ versus generates compartmentalized Ca2+ messengers remains unresolved.
  • Biogenic mechanism setting orientation unknown
  • Endogenous trigger for lysosomal trafficking undefined
  • Integration of enzyme vs receptor roles in a single cell not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0016787 hydrolase activity 3 GO:0060089 molecular transducer activity 3 GO:0009975 cyclase activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005829 cytosol 2 GO:0005764 lysosome 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CD16CD31

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CD38 functions as a bifunctional ectoenzyme that catalyzes both the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a Ca2+-mobilizing second messenger acting independently of inositol trisphosphate. It also functions as a receptor capable of mediating transmembrane signals and can be internalized in response to appropriate stimuli. Biochemical ectoenzyme assays, internalization experiments, functional antibody ligation studies in hematopoietic cells FASEB journal High 8903511
1997 The topological paradox of CD38's ectocellular catalytic domain synthesizing the intracellular messenger cADPR may be resolved by two mechanisms: (a) influx of extracellular cADPR across the plasma membrane to reach ryanodine-sensitive intracellular stores, and (b) NAD+-induced internalization of CD38 following membrane oligomerization, importing cADPR metabolism to an intracellular compartment, as observed in lymphoid B cells. Biochemical fractionation, NAD+-induced internalization experiments in lymphoid B cells, cerebellar granule cell Ca2+ signaling studies The international journal of biochemistry & cell biology Medium 9438379
1994 CD38 ligation on murine B cells stimulates protein tyrosine kinase activity but does not mobilize intracellular calcium stores and is not coupled to generation of inositol phosphates, indicating CD38 signals through a distinct pathway from classical PLC-coupled receptors. Calcium flux assays, inositol phosphate measurements, protein tyrosine phosphorylation assays in murine B cells using mitogenic anti-CD38 antibody NIMR-5 Immunology Medium 7875731
2001 CD38 ligation on human NK cells activates a signaling cascade including intracellular Ca2+ elevation, tyrosine phosphorylation of CD3-zeta, FcεRIγ, ZAP-70, and c-Cbl, and induces IFN-γ and GM-CSF secretion and cytolytic function. These CD38-mediated signals were absent in CD16-negative NK cell lines, establishing that CD38 requires CD16 (FcγRIIIA) as a co-signaling partner in NK cells. Calcium flux assays, tyrosine phosphorylation assays, cytokine secretion assays, cytotoxicity assays, genetic complementation of CD16-negative NK lines with CD16 expression International immunology Medium 11282979
2002 CD38 physically associates with CD16 on the surface of human NK cells, as demonstrated by FRET and cocapping experiments. Functional CD16 is necessary and sufficient for CD38 to control an activation pathway including calcium fluxes, ZAP-70 and MAPK phosphorylation, IFN-γ secretion, and cytotoxic responses, establishing CD38 as a receptor that signals through lineage-specific co-association with professional signaling molecules. FRET, cocapping, calcium flux, tyrosine phosphorylation, IFN-γ secretion, cytotoxicity assays in CD16+ and CD16- NK variants Blood High 11895784
2008 During immunological synapse (IS) formation, CD38 redistributes to the T cell–APC contact area in an antigen-dependent manner via Lck-mediated signals. Two distinct pools of CD38 exist—one at the plasma membrane and one in recycling endosomes—and both are recruited to the IS. CD38 overexpression increases antigen-induced intracellular Ca2+ release; siRNA knockdown reduces it. CD38 blockade inhibits IL-2 and IFN-γ production, PKCθ phosphorylation (Thr538), and PKCθ recruitment to the IS. Confocal microscopy, CD38-GFP live imaging, siRNA knockdown, Ca2+ flux assays, cytokine ELISA, PKCθ phosphorylation assays in human T cells and B cells Blood High 18212246
2012 CD38 exists in two opposing membrane orientations on cell surfaces: the canonical type II orientation (catalytic C-terminal domain extracellular) and a type III orientation (catalytic domain facing intracellularly). Site-directed mutagenesis of cationic residues in the N-terminal segment converts the mixed type II/III distribution to exclusively type III. Expression of type III CD38 increases intracellular cADPR concentrations, establishing the type III orientation as critical for intracellular Ca2+ signaling. Orientation-specific antibodies against N-terminal segment, site-directed mutagenesis, intracellular cADPR measurement in transfected HL-60 cells, monocytes, and U937 cells stimulated with IFN-γ Science signaling High 22969159
2011 CD38 activity generates the second messengers NAADP and cADPR. Gene silencing of CD38 did not inhibit NAADP synthesis in intact Jurkat T cells or in thymus/spleen from CD38 knockout mice, but in vitro CD38 efficiently catalyzed both NAADP formation (by base-exchange) and NAADP degradation. This establishes that in vivo CD38 functions as a NAADP-degrading rather than NAADP-synthesizing enzyme, likely preventing desensitizing NAADP levels. CD38 gene silencing (siRNA), CD38 knockout mouse tissues, in vitro enzymatic assays for NAADP formation and degradation FEBS letters Medium 22020217
2018 CD38 produces NAADP in the endolysosomal compartment. Nanobody-induced endocytosis of CD38 via a clathrin-dependent pathway delivers CD38 to lysosomes and elevates cellular NAADP levels. A lysosome-targeted CD38 variant is substantially more active in raising NAADP levels than wild-type CD38, and nicotinic acid supplementation further increases NAADP production, demonstrating that CD38 compartmentalization and substrate access—rather than enzyme activation—regulate NAADP production. Nanobody-directed endocytosis, lysosome-specific CD38 targeting constructs, intracellular NAADP measurement, clathrin inhibitor studies in human cell lines The Journal of biological chemistry High 29632067
2016 Crystal structures of CD38 complexed with anti-CD38 nanobodies identified three separate epitopes on the carboxyl (catalytic) domain of CD38. Chromobody (nanobody-fluorescent protein fusions) tools confirmed high CD38 expression on malignant MM cells. An immunotoxin (nanobody fused to bacterial toxin PE38) showed selective cytotoxicity against MM cells at picomolar concentrations. X-ray crystallography of CD38–nanobody complexes, flow cytometry quantification with chromobodies, in vitro cytotoxicity assays with immunotoxin Scientific reports High 27251573
2001 CD38 functions as a receptor that interacts with CD31 (PECAM-1) on the surface of leukocytes, mediating adhesion and signaling. The CD38–CD31 interaction constitutes a ligand–receptor pair governing leukocyte adhesion and transmembrane signaling. Receptor-ligand binding studies, adhesion assays, signaling assays in leukocytes Leukemia research Medium 11137554
2008 CD38 expression on CLL cells is upregulated by contact with activated CD4+ T cells, is higher in pseudofollicle-containing tissues, and marks proliferating CLL cells associated with CD31+ vascular endothelial cells. This establishes CD38 expression as dynamically regulated by the tumor microenvironment through T cell contact. Flow cytometry, tissue immunohistochemistry, in vitro co-culture of CLL cells with activated CD4+ T cells, comparison of tissue vs. blood CD38 levels Blood Medium 18326821
2012 LPS induces CD38 upregulation at the mRNA level in J774 macrophages via the JAK-STAT pathway and simultaneously causes CD38 shedding from the plasma membrane into the extracellular space via metalloproteinase-9 (MMP-9), as demonstrated by MMP-9 inhibitor blockade of CD38 release. Flow cytometry, RT-PCR, JAK-STAT pathway inhibitors, metalloproteinase-9 inhibitor, ELISA for soluble CD38 in culture supernatant Molecules and cells Medium 23184288
2011 PI3K p110δ regulates CD38 expression on regulatory T cells (Tregs): p110δ-inactivated Tregs fail to develop CD38high cells. CD38high Tregs display superior suppressive activity and upregulate CD73 compared to CD38low Tregs. CD38 marks Tregs with high suppressive capacity downstream of PI3K p110δ signaling. Transcriptome comparison of wild-type vs. p110δ(D910A) Tregs, flow cytometry, Treg suppression assays, CD38+/- heterozygous mouse analysis PloS one Medium 21390257
2017 CD38 promotes angiotensin II-induced cardiac hypertrophy by inhibiting SIRT3 expression and activating Ca2+-NFAT signaling. CD38 knockout mice show significantly reduced cardiac hypertrophy and fibrosis after Ang-II infusion compared to wild-type. In H9c2 cardiomyocytes, CD38 RNAi knockdown decreases ANF and BNP gene expression, reduces ROS generation, elevates SIRT3, activates FOXO3 antioxidant pathway, and markedly reduces Ang-II-induced intracellular Ca2+ release and NFATc4 nuclear translocation. CD38 knockout mice with osmotic mini-pump Ang-II infusion, cardiac histology, RNAi knockdown in H9c2 cells, intracellular Ca2+ measurement, Western blotting for SIRT3/FOXO3/NFATc4/ERK/AKT Journal of cellular and molecular medicine Medium 28296029
2020 During sepsis resolution, CD38 levels increase to produce Ca2+-signaling messengers (NAADP, ADPR, cADPR) from NAD(P)+. These second messengers induce tristetraprolin (TTP) expression, which then downregulates CD38. Sirt1-dependent TTP deacetylation (activated by increased NAD+ levels) suppresses acute inflammation, decreases Rheb, inhibits mTORC1, and induces autophagolysosomes for bacterial clearance, defining a CD38–TTP feedback loop in inflammation resolution. Sepsis mouse models, CD38 and TTP KO mice, Sirt1 inhibition, mTORC1 signaling assays, autophagolysosome formation assays, second messenger measurements Cell reports Medium 31995750
2018 CD38 enzymatic activity (NADase) depletes intracellular NAD+ in prostate cancer cells, causing cell-cycle arrest with p21Cip1 upregulation, diminishing glycolytic and mitochondrial metabolism, activating AMPK, and inhibiting fatty acid/lipid synthesis. Expression of an NAD+ hydrolase-deficient CD38 mutant failed to reproduce these metabolic effects, establishing NADase activity as the mechanistic basis. CD38 overexpression and NADase-deficient mutant in prostate cancer cell lines, NAD+ measurement, cell-cycle analysis, metabolic flux assays (Seahorse), AMPK phosphorylation, transcriptome profiling Molecular cancer research : MCR High 30076241
2018 CD38 overexpression in prostate epithelial cells depletes extracellular (but not intracellular) NAD+ levels, as confirmed by wild-type vs. NAD+ hydrolase-deficient mutant comparisons in cell lines and by NAD+ measurements in urogenital tissues from CD38 knockout vs. wild-type mice. Inducible CD38 overexpression, NADase-deficient CD38 mutant, NAD+ measurements in culture medium and tissues, CD38 KO mouse urogenital tissue analysis Cancer & metabolism High 30258629
2020 Pro-inflammatory M1-like macrophages accumulate in visceral adipose tissue and liver during aging and express high levels of CD38 with enhanced CD38-dependent NADase activity, thereby reducing tissue NAD+ levels. Senescent cell-derived SASP cytokines induce macrophages to proliferate and upregulate CD38, establishing a causal chain: senescence → SASP → macrophage CD38 induction → NAD+ decline. Flow cytometry of tissue macrophage subsets, CD38 NADase activity assays, senescent cell depletion, SASP cytokine treatment of macrophages, tissue NAD+ measurement in aged mice Nature metabolism High 33199924
2018 In human macrophages and monocytes, CD38 expression is robustly induced by LPS ± IFN-γ but not by IL-4. Pharmacologic and/or genetic CD38 loss-of-function significantly reduced secretion of inflammatory cytokines IL-6 and IL-12p40 and glycolytic activity in primary human macrophages. LPS/IFN-γ/IL-4 stimulation of human primary macrophages, siRNA knockdown, pharmacological inhibition, ELISA for cytokines, glycolysis assays Frontiers in immunology Medium 30042766
2018 Daratumumab (anti-CD38 antibody) induces rapid CD38 protein internalization and degradation on NK cells, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by daratumumab promotes monocyte activation, increasing T-cell costimulatory molecules (CD86/CD80) and enhancing anti-MM phagocytosis. Flow cytometry of NK cell CD38 expression after daratumumab treatment, monocyte activation assays, co-culture cytotoxicity/phagocytosis assays ex vivo and in vivo (mouse xenograft) Leukemia Medium 32296125
2018 Daratumumab treatment causes CD38 internalization on MM cell surfaces via dynamin-dependent endocytosis and impairs MM cell adhesion; this adhesion impairment can be rescued by the endocytosis inhibitor Dynasore. CD38 internalization-mediated loss of adhesion increases MM cell sensitivity to bortezomib. Flow cytometry of surface CD38 after daratumumab, Dynasore endocytosis inhibitor rescue of adhesion, in vitro and in vivo bortezomib combination studies Oncoimmunology Medium 30288349
2019 CD38 modulates B-cell receptor (BCR) signaling in CLL: interference with CD38 downregulates Syk, BTK, PLCγ2, ERK1/2, and AKT phosphorylation. Daratumumab additionally induces direct apoptosis of primary CLL cells partially dependent on FcγR cross-linking, beyond its immune-effector mechanisms. Immunoblotting of BCR signaling intermediates after CD38 targeting/blockade, apoptosis assays, FcγR blocking experiments, in vivo CLL xenograft model Clinical cancer research Medium 30940652
2022 CD38 elevation in alveolar epithelial cells (AECs) downregulates intracellular NAD+, impairing NAD-dependent cellular activities and promoting cellular aging phenotypes and lung fibrosis. Genetic and pharmacological inactivation of CD38 improved NAD-dependent events and ameliorated bleomycin-induced lung fibrosis in mice. scRNA-seq, Western blotting, flow cytometry, CD38 KO mice, pharmacological CD38 inhibition, bleomycin fibrosis model, NAD+ measurement American journal of respiratory and critical care medicine Medium 35687485
2023 CD38 expression in the ovary increases with reproductive age, and CD38 knockout mice exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity. The larger ovarian reserve results from a prolonged window of follicle formation during early development, establishing that CD38-dependent NAD+ consumption accelerates the depletion of ovarian reserve. CD38 KO mouse reproductive phenotyping, ovarian NAD+ measurement, primordial follicle counting, fecundity assays iScience Medium 37822499
2023 Pharmacological inhibition or genetic knockout of CD38 in chondrocytes increases the intracellular NAD+:NADH ratio and reduces catabolic responses to IL-1β. In vivo, CD38-deficient mice show significantly reduced cartilage degradation, synovial inflammation, osteophyte formation, subchondral bone sclerosis, and pain-like behavior after joint injury. CD38 overexpression and pharmacological inhibition in chondrocytes, NAD+:NADH ratio measurement, catabolic gene expression, CD38 KO mice with DMM surgery, cartilage histology, pain behavior assays Arthritis & rheumatology Medium 36103412
2022 High CD38 expression increases cellular ROS levels and induces oxidative degradation of dihydrofolate reductase (DHFR) via sulfonation of Cys7, leading to DHFR degradation through autophagy and non-canonical proteasome pathways. This DHFR loss increases cellular susceptibility to ferroptosis. Mutation of DHFR Cys7 to alanine abolishes ROS-induced degradation, and NMN supplementation (to restore NAD+) prevents DHFR degradation and ferroptosis susceptibility. CD38 overexpression, ROS measurement, site-directed mutagenesis of DHFR Cys7, autophagy/proteasome pathway inhibitors, ferroptosis assays, aged vs. young bone-marrow-derived macrophage comparisons, NMN supplementation rescue Cell death & disease Medium 36351893
2022 TNB-738, a biparatopic anti-CD38 antibody binding two non-competing epitopes simultaneously, potently inhibits CD38 ecto-enzyme activity, boosting intracellular NAD+ levels and sirtuin (SIRT) activities without depleting CD38-expressing cells (due to silenced IgG4 Fc). Fluorescence spectroscopy enzymatic activity assays, intracellular NAD+ measurement, sirtuin activity assays, ADCC/CDC assays confirming lack of cell depletion, SPR binding studies mAbs Medium 35867844
2023 HexaBody-CD38 binds a unique epitope on CD38 (identified by co-crystallization) and strongly inhibits CD38 cyclase activity. The E430G Fc mutation facilitates antibody hexamerization upon cell-surface binding, increasing C1q recruitment and potentiating complement-dependent cytotoxicity (CDC) compared to daratumumab. Co-crystallization of HexaBody-CD38 with CD38, fluorescence spectroscopy for cyclase inhibition, CDC/ADCC/ADCP/apoptosis flow cytometry assays, patient-derived xenograft mouse models EBioMedicine High 37379657
2011 In vitro activation of CLL cells through CD38 drives proliferation and chemotaxis via a signaling pathway that includes ZAP-70 and ERK1/2, establishing CD38 as a functional signal transducer promoting CLL cell survival and migration. CD38 ligation assays in CLL cells, Western blotting of ZAP-70 and ERK1/2 phosphorylation, proliferation and chemotaxis assays Blood Medium 21765022
2001 Human monocytes rapidly degrade extracellular NAD+ to nicotinamide and ADP-ribose via surface CD38 (NAD+-glycohydrolase activity). Anti-CD38 mAb ligation induces CD38 internalization and shedding. Monocyte-to-macrophage differentiation downregulates surface CD38 expression at the transcriptional level, correlating with reduced NADase activity. NAD+ degradation product analysis (HPLC), flow cytometry, RT-PCR, anti-CD38 mAb internalization assays, monocyte-to-macrophage differentiation experiments European journal of biochemistry Medium 11683883
2016 CD38 knockout mice exhibit deficits in spatial memory (Morris water maze), contextual fear conditioning, and object recognition memory. However, hippocampal long-term potentiation and long-term depression are intact in CD38−/− mice, indicating CD38 is required for hippocampus-dependent learning and memory through mechanisms independent of synaptic plasticity. Morris water maze, contextual fear conditioning, object recognition tests in CD38−/− mice, electrophysiological LTP/LTD recordings in hippocampal slices Molecular brain Medium 26856703

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. The New England journal of medicine 948 26308596
2017 CD38 antibodies in multiple myeloma: back to the future. Blood 388 29118010
2020 Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nature metabolism 352 33199924
2016 Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunological reviews 282 26864107
2020 CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity. Frontiers in immunology 265 33329591
2020 Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. The New England journal of medicine 263 32937047
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2018 The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends in pharmacological sciences 182 29482842
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2018 CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions. Frontiers in immunology 175 30042766
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2019 Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab. Cells 120 31779273
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2018 Clonally diverse CD38+HLA-DR+CD8+ T cells persist during fatal H7N9 disease. Nature communications 108 29483513
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2023 NADase CD38 is a key determinant of ovarian aging. Nature aging 75 38129670
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2018 Immunomodulatory effects of CD38-targeting antibodies. Immunology letters 75 29702148
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2020 Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting. Leukemia 71 32296125
2001 Signaling through CD38 induces NK cell activation. International immunology 71 11282979
1997 The CD38/cyclic ADP-ribose system: a topological paradox. The international journal of biochemistry & cell biology 71 9438379
2017 CD38 promotes angiotensin II-induced cardiac hypertrophy. Journal of cellular and molecular medicine 70 28296029
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2022 CD38: A Significant Regulator of Macrophage Function. Frontiers in oncology 63 35251964
2022 The CD38 glycohydrolase and the NAD sink: implications for pathological conditions. American journal of physiology. Cell physiology 62 35138178
2021 CD38 and Regulation of the Immune Response Cells in Cancer. Journal of oncology 61 33727923
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2022 CD38 Mediates Lung Fibrosis by Promoting Alveolar Epithelial Cell Aging. American journal of respiratory and critical care medicine 59 35687485
2018 Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology 59 30288349
2013 The roles of oxytocin and CD38 in social or parental behaviors. Frontiers in neuroscience 52 23335873
2018 CD38 Inhibits Prostate Cancer Metabolism and Proliferation by Reducing Cellular NAD+ Pools. Molecular cancer research : MCR 50 30076241
2021 Vaccine-induced ICOS+CD38+ circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways. Cell reports. Medicine 48 34095875
2016 Impaired learning and memory in CD38 null mutant mice. Molecular brain 48 26856703
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2020 Resistance Mechanisms Towards CD38-Directed Antibody Therapy in Multiple Myeloma. Journal of clinical medicine 41 32331242
2019 CD38, CD157, and RAGE as Molecular Determinants for Social Behavior. Cells 41 31881755
2008 CD38 and CD157 ectoenzymes mark cell subsets in the human corneal limbus. Molecular medicine (Cambridge, Mass.) 41 19052657
2023 Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. Cancer medicine 39 37840445
1995 CD38 expression on mouse T cells: CD38 defines functionally distinct subsets of alpha beta TCR+CD4-CD8- thymocytes. International immunology 38 7734417
2019 Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 37 30940652
2018 CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome. The Journal of biological chemistry 37 29632067
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2020 CD38 in cancer-associated fibroblasts promotes pro-tumoral activity. Laboratory investigation; a journal of technical methods and pathology 35 32612286
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2021 CD38 in Advanced Prostate Cancers. European urology 34 33678520
2020 Cross-talk between CD38 and TTP Is Essential for Resolution of Inflammation during Microbial Sepsis. Cell reports 34 31995750
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2023 CD38-Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 30 37485647
2022 Expanding anti-CD38 immunotherapy for lymphoid malignancies. Journal of experimental & clinical cancer research : CR 30 35765110
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2018 Phenotyping and Target Expression Profiling of CD34+/CD38- and CD34+/CD38+ Stem- and Progenitor cells in Acute Lymphoblastic Leukemia. Neoplasia (New York, N.Y.) 29 29772458
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2022 Targeting CD38 in Neoplasms and Non-Cancer Diseases. Cancers 27 36077708
2021 IFN-γ and CD38 in Hyperprogressive Cancer Development. Cancers 27 33467713
2024 Intratumoral CD38+CD19+B cells associate with poor clinical outcomes and immunosuppression in patients with pancreatic ductal adenocarcinoma. EBioMedicine 26 38608514
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2014 CD38 and bone marrow microenvironment. Frontiers in bioscience (Landmark edition) 26 24389178
2023 Preclinical anti-tumour activity of HexaBody-CD38, a next-generation CD38 antibody with superior complement-dependent cytotoxic activity. EBioMedicine 25 37379657
2024 The frequency of CD38+ alveolar macrophages correlates with early control of M. tuberculosis in the murine lung. Nature communications 24 39358361
2021 Molecular dynamics of targeting CD38 in multiple myeloma. British journal of haematology 24 33570193
2020 CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond. International journal of molecular sciences 24 32531894
2018 CD38 affects the biological behavior and energy metabolism of nasopharyngeal carcinoma cells. International journal of oncology 24 30535454
2011 CD38 through the life of a murine B lymphocyte. IUBMB life 24 21901817
2023 CD38 regulates ovarian function and fecundity via NAD+ metabolism. iScience 23 37822499
2020 CD38 downregulation modulates NAD+ and NADP(H) levels in thermogenic adipose tissues. Biochimica et biophysica acta. Molecular and cell biology of lipids 23 33010451
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2024 CD38 as theranostic target in oncology. Journal of translational medicine 21 39501292
2019 Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γ Expression in CD38-/- Mice. Journal of immunology research 21 30915370
2022 TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. mAbs 20 35867844
2022 Oxidative degradation of dihydrofolate reductase increases CD38-mediated ferroptosis susceptibility. Cell death & disease 19 36351893
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