Affinage

NAMPT

Nicotinamide phosphoribosyltransferase · UniProt P43490

Round 2 corrected
Length
491 aa
Mass
55.5 kDa
Annotated
2026-04-29
130 papers in source corpus 32 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NAMPT is the rate-limiting enzyme of the mammalian NAD+ salvage pathway, catalyzing the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), and thereby governing intracellular NAD+ pools that fuel sirtuins (SIRT1–4), PARP1, and CD38 (PMID:12555668, PMID:17889652, PMID:16783373). Intracellular NAMPT localizes to both the cytosol and the mitochondrial matrix of neurons and cardiomyocytes, where it sustains compartment-specific NAD+ levels critical for bioenergetics, neuronal survival, and circadian clock amplitude (PMID:31553812, PMID:36441480, PMID:36996103); its activity is post-translationally enhanced by SIRT6- and SIRT1-mediated deacetylation and transcriptionally regulated by STAT1, REV-ERBα/β–E4BP4, lamin A/C-dependent chromatin accessibility, and miR-146a (PMID:30514106, PMID:36797299, PMID:33976173, PMID:35036997, PMID:35241643, PMID:36099415). The secreted extracellular form (eNAMPT), released in extracellular vesicles, exerts both enzymatic effects—supporting β-cell insulin secretion and vascular NAD+ supply during aging—and enzyme-independent cytokine-like functions including monocyte activation via NF-κB/MAPK/STAT3 signaling, neutrophil NADPH oxidase priming through p38/ERK-dependent p40/p47 translocation and Rac activation, M2 macrophage polarization, and CCR5-dependent muscle stem cell proliferation during tissue regeneration (PMID:17983582, PMID:31204283, PMID:17237424, PMID:21518975, PMID:25368373, PMID:33568815). In macrophages, NAMPT stabilizes HIF-1α to promote M2 tumor-associated macrophage polarization and efferocytosis, while its loss enhances STING-mediated type I interferon signaling and anti-tumor immunity (PMID:38308188).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    The gene was first identified as a secreted cytokine (PBEF) that synergizes with SCF and IL-7 to promote pre-B-cell colony formation, establishing its extracellular signaling role before its enzymatic function was known.

    Evidence cDNA library cloning from human peripheral blood lymphocytes with in vitro B-cell colony assay

    PMID:8289818

    Open questions at the time
    • Receptor for the cytokine activity was not identified
    • Mechanism of synergy with SCF/IL-7 undefined
  2. 2002 High

    Reconstitution of NAMPT enzymatic activity—conversion of nicotinamide + PRPP to NMN—reframed PBEF as the rate-limiting NAD+ salvage enzyme, fundamentally changing the understanding of its biology from pure cytokine to metabolic enzyme.

    Evidence Direct enzymatic activity assay and bacterial complementation of NAmPRTase-defective strain

    PMID:12555668

    Open questions at the time
    • How cytokine activity relates to enzymatic activity was unresolved
    • Structural basis of catalysis unknown at this point
  3. 2004 High

    Discovery that NAMPT inhibits neutrophil apoptosis in response to inflammatory stimuli demonstrated a pro-survival role in innate immune cells distinct from its B-cell effects.

    Evidence Antisense oligonucleotide knockdown and recombinant protein treatment with caspase activity assays in human neutrophils

    PMID:15124023

    Open questions at the time
    • Whether this anti-apoptotic effect is enzymatic or cytokine-mediated was not resolved
    • Receptor and signaling pathway not identified
  4. 2006 High

    The crystal structure revealed NAMPT as a dimeric type II phosphoribosyltransferase, providing the structural framework for understanding catalysis and enabling rational inhibitor design.

    Evidence X-ray crystallography with and without NMN product bound

    PMID:16783373

    Open questions at the time
    • Structural basis of the cytokine-like (enzyme-independent) activity remained unexplained
  5. 2007 High

    A series of studies established the NAMPT→NAD+→sirtuin axis as a central signaling conduit: NAMPT controls mitochondrial NAD+ and cell survival via SIRT3/SIRT4 under fasting, extends vascular smooth muscle cell lifespan via SIRT1-mediated p53 deacetylation, and eNAMPT regulates pancreatic β-cell insulin secretion through its enzymatic product NMN.

    Evidence Nampt+/− mice with NMN rescue for insulin secretion; fasting/fractionation/siRNA for mitochondrial sirtuins; dominant-negative SIRT1 epistasis for vascular senescence

    PMID:17307730 PMID:17889652 PMID:17983582

    Open questions at the time
    • Whether eNAMPT has a dedicated receptor was unresolved
    • Tissue-specific differences in NAMPT dependence not yet mapped
  6. 2007 High

    Extracellular NAMPT was shown to activate monocytes and induce pro-inflammatory cytokines through p38/MEK1/NF-κB, establishing it as a dual-function molecule with both enzymatic and cytokine-like activities.

    Evidence Recombinant eNAMPT treatment of CD14+ monocytes with MAPK inhibitors and NF-κB activation assays

    PMID:17237424

    Open questions at the time
    • Whether this monocyte activation requires enzymatic activity was not dissected here
  7. 2009 High

    Vascular inflammation by eNAMPT was shown to require its enzymatic activity (NMN mimics the effect, APO866 blocks it), while separately, constitutive hepatocyte secretion of dimeric eNAMPT was documented, indicating continuous systemic release.

    Evidence ERK/NF-κB signaling in vascular smooth muscle cells with NMN/APO866; size exclusion chromatography and activity assay on secreted hepatocyte NAMPT

    PMID:19727662 PMID:19912992

    Open questions at the time
    • Mode of secretion (classical vs. non-classical) not determined
    • Relative contribution of different tissues to circulating eNAMPT unknown
  8. 2011 High

    Neutrophil NADPH oxidase priming by eNAMPT was definitively shown to be enzyme-independent—NMN and NAD cannot mimic it and APO866 cannot block it—acting instead through p38/ERK to translocate p40/p47 subunits and activate Rac, establishing a clear bifunctional paradigm for extracellular NAMPT.

    Evidence Membrane fractionation, Rac activation assay, MAPK inhibitors, and APO866 in human neutrophils

    PMID:21518975

    Open questions at the time
    • The receptor mediating enzyme-independent signaling in neutrophils was not identified
    • Structural determinants on NAMPT that mediate cytokine-like activity unknown
  9. 2014 High

    Two landmark studies addressed tissue-autonomous requirements: eNAMPT promoted M2 macrophage polarization via ERK1/2/STAT3/NF-κB independently of enzymatic activity (proven by enzymatic mutant), while neuron-specific NAMPT deletion caused hippocampal atrophy, gliosis, and memory deficits, demonstrating non-redundant intracellular NAD+ dependency in excitatory neurons.

    Evidence Enzymatically inactive NAMPT mutant in CLL-derived macrophage polarization assay; CaMKIIα-Cre Nampt conditional knockout with histology, electrophysiology, and behavioral testing

    PMID:24760840 PMID:25368373

    Open questions at the time
    • Receptor for enzyme-independent macrophage polarization not identified
    • Whether neuronal NAMPT loss phenotype is reversible with NMN supplementation untested in this study
  10. 2018 High

    SIRT6 was identified as a direct deacetylase of NAMPT, establishing a positive feedback loop where sirtuin activity enhances NAD+ biosynthesis by activating NAMPT.

    Evidence In vitro reconstitution of SIRT6-mediated NAMPT deacetylation with immunopurified NAMPT and recombinant SIRT6, validated by NAD(H) measurements in cancer cells

    PMID:30514106

    Open questions at the time
    • Specific acetylation sites on NAMPT targeted by SIRT6 not mapped
    • Whether this loop operates in non-cancer contexts was unclear
  11. 2019 High

    Multiple studies refined compartment-specific roles: NAMPT resides in the neuronal mitochondrial matrix maintaining a local NAD+ salvage pathway; eNAMPT circulates in extracellular vesicles and its supplementation from young to old mice extends lifespan; and balanced NAMPT dosage is critical in the heart where both gain and loss of function worsen heart failure.

    Evidence Subcellular fractionation and NMNAT knockdown in neurons; EV isolation with NAD+ assays and lifespan studies in mice; Nampt+/− and cardiac-specific transgenic mice under pressure overload

    PMID:31204283 PMID:31347918 PMID:31553812

    Open questions at the time
    • Mechanism of NAMPT import into mitochondria unknown (lacks canonical MTS)
    • Cargo-sorting mechanism for eNAMPT into EVs uncharacterized
    • Therapeutic window for NAMPT modulation in cardiac disease undefined
  12. 2021 High

    Transcriptional and receptor-level regulation was resolved: STAT1 drives NAMPT expression via the intronic NRE1 element in macrophages supporting anti-tumor glycolysis; REV-ERBα/β–E4BP4 controls circadian NAMPT expression in cardiomyocytes; and macrophage-derived eNAMPT acts through CCR5 on muscle stem cells to drive regeneration.

    Evidence STAT1 ChIP at NRE1 with myeloid-specific NRE1 KO and melanoma model; cardiomyocyte-specific Rev-erb DKO with ChIP; zebrafish NAMPT/CCR5 genetic perturbation with live imaging

    PMID:33568815 PMID:33976173 PMID:35036997

    Open questions at the time
    • Whether CCR5 is the receptor for enzyme-independent eNAMPT signaling in mammals not confirmed
    • How NRE1-dependent NAMPT expression differs between macrophage subtypes not fully explored
    • Whether E4BP4 directly binds Nampt regulatory elements or acts indirectly needs clarification
  13. 2021 High

    NAMPT-supplied NAD+ was linked to parthanatos: in psoriasis models, NAMPT fuels PARP1 hyperactivation and AIFM1 nuclear translocation, causing keratinocyte death and inflammation—demonstrating pathological consequences of excessive NAD+ availability.

    Evidence Zebrafish and human 3D skin models with genetic/pharmacological NAMPT inhibition, PARP activity measurement, AIFM1 localization

    PMID:34748530

    Open questions at the time
    • Whether NAMPT inhibition is therapeutically viable in human psoriasis untested
    • Relative contribution of PARP1 vs. other NAD+ consumers in this context unclear
  14. 2022 High

    Post-transcriptional and epigenetic control of NAMPT was elucidated: miR-146a directly suppresses NAMPT via 3′-UTR targeting within a mutual inhibitory loop with AMPK/NF-κB; and lamin A/C deficiency reduces NAMPT promoter chromatin accessibility, depleting NAD+ and impairing mitochondrial function in progeria.

    Evidence 3′-UTR luciferase assay with miR-146a and AMPK activators in vitro/in vivo; ATAC-seq of Lmna−/− MEFs and HGPS fibroblasts with NAD+/SIRT1/bioenergetics readouts

    PMID:35241643 PMID:36099415

    Open questions at the time
    • Whether chromatin accessibility changes at NAMPT are a cause or consequence of NAD+ depletion in progeria needs further dissection
    • Therapeutic potential of miR-146a inhibition for NAD+ restoration unexplored
  15. 2023 High

    SIRT1 was identified as a second sirtuin that directly deacetylates and activates NAMPT (complementing SIRT6), and tissue-specific circadian clock dependence on NAMPT was mapped—essential in brown adipose tissue, moderate in white adipose, absent in skeletal muscle.

    Evidence SIRT1-NAMPT Co-IP with deacetylation assay and nicotine-treated aging mice; adipose-specific Nampt KO with clock gene expression and metabolomics

    PMID:36797299 PMID:36996103

    Open questions at the time
    • Acetylation site specificity for SIRT1 vs. SIRT6 on NAMPT not compared
    • Basis for tissue-specific clock dependence on NAMPT unclear
  16. 2024 High

    Macrophage-intrinsic NAMPT was shown to stabilize HIF-1α for M2 TAM polarization and efferocytosis, while its absence activates STING/type I IFN signaling to enhance anti-tumor immunity—defining NAMPT as a myeloid immune checkpoint; separately, NAMPT→NAD+→SIRT2-mediated LDHA deacetylation was linked to lactate production and follicular development in PCOS.

    Evidence Myeloid-specific Nampt KO with scRNA-seq of tumor microenvironment and STING pathway analysis; Co-IP of LDHA acetylation with FK866/NMN in PCOS rat model

    PMID:38308188 PMID:39489197

    Open questions at the time
    • Whether NAMPT-targeted myeloid therapy synergizes with immune checkpoint inhibitors in patients is untested
    • SIRT2-LDHA-lactate axis in PCOS based on single study with Co-IP, awaits independent validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of eNAMPT's enzyme-independent cytokine-like activity, the mechanism of NAMPT translocation into the mitochondrial matrix, the full receptor repertoire for eNAMPT signaling across tissues (only CCR5 identified in zebrafish muscle stem cells), and whether therapeutic NAMPT modulation can achieve tissue-selective NAD+ control without pathological consequences.
  • Structural determinants for cytokine vs. enzyme activity on the NAMPT dimer uncharacterized
  • Mitochondrial import mechanism unknown
  • Mammalian receptor for enzyme-independent eNAMPT signaling not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0005739 mitochondrion 3 GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9909396 Circadian clock 2 R-HSA-8953854 Metabolism of RNA 1
Partners
CCR5HIF1APARP1SIRT1SIRT2SIRT3SIRT6STAT1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NAMPT (then called PBEF) was originally cloned from a human peripheral blood lymphocyte cDNA library as a secreted 52-kDa protein that synergizes with stem cell factor and IL-7 to enhance pre-B-cell colony formation, establishing it as a cytokine acting on early B-lineage precursor cells. cDNA library screening, expression in COS7/PA317 cells, in vitro B-cell colony formation assay Molecular and cellular biology High 8289818
2002 PBEF/NAMPT was identified as a nicotinamide phosphoribosyltransferase (NAmPRTase), catalyzing the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), an intermediate in NAD biosynthesis; the mouse gene complemented a NAmPRTase-defective bacterial strain, confirming enzymatic function. Enzymatic activity assay, bacterial complementation assay, antibody panel characterization European journal of immunology High 12555668
2006 Crystal structure of NAMPT (with and without NMN bound) revealed it is a dimeric type II phosphoribosyltransferase, providing structural insights into the enzymatic mechanism of NMN synthesis. X-ray crystallography Nature structural & molecular biology High 16783373
2007 Haplodeficiency and chemical inhibition of NAMPT cause defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets; extracellular NAMPT (eNAMPT) exerts its effects through NAD biosynthetic activity (producing NMN) rather than insulin-mimetic hormone activity, as administration of NMN rescues the defects. Nampt heterozygous knockout mice, chemical inhibition, NMN rescue experiments, in vitro and in vivo glucose-stimulated insulin secretion assays Cell metabolism High 17983582
2007 NAMPT is the rate-limiting enzyme in the NAD+ salvage pathway from nicotinamide in mammals; increased NAMPT expression under fasting conditions elevates mitochondrial NAD+ levels and provides protection against cell death, requiring mitochondrial NAD+-dependent deacetylases SIRT3 and SIRT4. Fasting experiments in rodents, subcellular fractionation, siRNA knockdown, cell viability assays Cell High 17889652
2004 PBEF/NAMPT functions as a novel inhibitor of neutrophil apoptosis in response to inflammatory stimuli (LPS, IL-1, GM-CSF, IL-8, TNF-α); antisense oligonucleotide blockade of PBEF translation completely abrogates LPS-induced neutrophil apoptosis delay, and inhibition is associated with reduced caspase-8 and caspase-3 activity. Antisense oligonucleotide, recombinant protein treatment, caspase activity assays, apoptosis quantification The Journal of clinical investigation High 15124023
2007 Extracellular visfatin (NAMPT) activates human leukocytes and induces cytokine production (IL-1β, TNF-α, IL-6) in CD14+ monocytes, increases costimulatory molecule expression (CD54, CD40, CD80), and activates NF-κB via p38 and MEK1 MAPK pathways. Recombinant protein treatment, MAPK inhibitor experiments, NF-κB activation assays, cytokine ELISA, flow cytometry Journal of immunology High 17237424
2007 NAMPT-mediated NAD+ biosynthesis extends the lifespan of human vascular smooth muscle cells through increased SIRT1 activity and reduced p53 acetylation (K382) and degradation; a dominant-negative SIRT1 abrogates the anti-aging effect, placing NAMPT upstream of SIRT1 in this pathway. Nampt gene overexpression, FK866 inhibitor, dominant-negative SIRT1 transduction, senescence-associated β-galactosidase assay, p53 acetylation western blot The Journal of biological chemistry High 17307730
2009 Extracellular NAMPT activates pro-inflammatory signaling in human vascular smooth muscle cells through its intrinsic enzymatic activity: it induces iNOS via sequential ERK1/2 and NF-κB activation; exogenous NMN (the product of NAMPT) mimics these effects, while the NAMPT inhibitor APO866 blocks them, demonstrating the enzymatic activity is required. Western blotting, EMSA (NF-κB), ERK inhibitor PD98059, NF-κB inhibitor, APO866, exogenous NMN treatment Diabetologia High 19727662
2009 Human hepatocytes constitutively release NAMPT into the extracellular compartment; secreted NAMPT exists primarily as the dimeric form and retains enzymatic activity; hepatocyte NAMPT secretion is not regulated by glucose, insulin, or TNF-α. Size exclusion chromatography, in vitro enzymatic activity assay, HepG2 cells and primary human hepatocytes Biochemical and biophysical research communications Medium 19912992
2011 Extracellular PBEF/NAMPT primes neutrophils for augmented NADPH oxidase-dependent respiratory burst by promoting membrane translocation of cytosolic NADPH oxidase subunits p40 and p47 (but not p67), inducing p40 phosphorylation on Thr154, and activating Rac GTPase; this priming is dependent on p38 and ERK MAPK but is independent of NAMPT's NAD-generating capacity (NMN or NAD cannot recapitulate the effect, and APO866 does not block it). Membrane fractionation, phosphorylation assays, Rac GTPase activation assay, MAPK inhibitors, APO866 inhibitor, ROS measurement Journal of immunology High 21518975
2013 NAMPT enzymatic activity regulates GADD45A expression through the NAMPT→NAD+→SIRT1→FOXO3a acetylation axis: NAMPT overexpression decreases GADD45A expression, while NAMPT inhibition by FK866 or SIRT1 knockdown increases GADD45A; the increase involves acetylation of FOXO3a. NAMPT overexpression, FK866 inhibitor, SIRT1 shRNA, western blotting, gene expression analysis Biochemical and biophysical research communications Medium 22430142
2014 Extracellular NAMPT (eNAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia independently of its enzymatic activity, as demonstrated by use of an enzymatically inactive mutant; eNAMPT is produced by CLL lymphocytes upon BCR, TLR, and NF-κB signaling activation and polarized macrophages activate ERK1/2, STAT3, and NF-κB signaling. Enzymatically inactive NAMPT mutant, monocyte differentiation assays, flow cytometry, cytokine profiling, signaling pathway western blots Blood High 25368373
2014 Forebrain excitatory neurons primarily use intracellular NAMPT-mediated NAD+ biosynthesis for their survival and function; CaMKIIα-specific Nampt knockout mice develop hippocampal/cortical atrophy, astrogliosis, microgliosis, abnormal CA1 dendritic morphology, altered intrahippocampal connectivity, and behavioral impairments including memory deficits. Conditional (CaMKIIα-Cre) Nampt knockout mice, histology, electrophysiology, behavioral testing The Journal of neuroscience High 24760840
2018 SIRT6 directly deacetylates NAMPT (identified by immunopurification and incubation with recombinant SIRT6), and this deacetylation upregulates NAMPT enzymatic activity, increasing intracellular NAD(H) levels and protecting cancer cells against oxidative stress. Immunopurification, recombinant SIRT6 incubation, SIRT6 overexpression/silencing in cancer cells, NAD(H) measurement, enzymatic activity assay FASEB journal High 30514106
2019 Extracellular NAMPT (eNAMPT) is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans; EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis; supplementing eNAMPT-containing EVs from young mice improves physical activity and extends lifespan in aged mice. EV isolation, internalization assays, NAD+ measurement, adipose-tissue-specific NAMPT overexpression, lifespan and wheel-running experiments in mice Cell metabolism High 31204283
2019 Both loss and gain of Nampt function exacerbate pressure-overload-induced heart failure; Nampt knockdown diminishes mitochondrial NAD content and ATP production in cardiomyocytes; Nampt overexpression increases Sirt1 expression and activity, causing excessive suppression of mitochondrial proteins and metabolic genes plus upregulation of inflammatory cytokines. Nampt+/- heterozygous KO mice, cardiac-specific Nampt transgenic mice, pressure overload model, mitochondrial NAD/ATP measurement, protein acetylation analysis American journal of physiology. Heart and circulatory physiology High 31347918
2019 NAMPT is localized within the mitochondrial matrix of neurons (alongside NMNAT3), where it maintains an intact NAD+ salvage pathway; NMNAT3 knockdown has a larger effect on mitochondrial respiration than NMNAT1/2, while NMNAT1/2 affect glycolytic flux more; mitochondrial, cytoplasmic, and non-compartmental NAMPT overexpression all provide comparable neuronal protection and suppression of apoptosis-inducing factor translocation after ischemia. Subcellular fractionation, siRNA knockdown of NMNAT1-3 and NAMPT, confocal microscopy, oxygen glucose deprivation model, mitochondrial respiration assay Journal of neurochemistry High 31553812
2021 Macrophage-derived eNAMPT (secreted from a specific 'dwelling' macrophage subset) is required for muscle stem cell (satellite cell) proliferation and muscle regeneration in zebrafish; eNAMPT acts through the C-C motif chemokine receptor CCR5 expressed on muscle stem cells. Zebrafish muscle injury models, single-cell profiling, real-time in vivo imaging, genetic perturbation of NAMPT/CCR5 Nature High 33568815
2021 Circadian clock components REV-ERBα/β repress E4BP4, which directly controls the circadian expression of Nampt via distal cis-regulatory elements; loss of Rev-erbs induces E4BP4 and downregulates Nampt, reducing NAD+ production via the salvage pathway and causing dilated cardiomyopathy. Cardiomyocyte-specific Rev-erb double knockout mice, chromatin occupancy (ChIP), NAD+ measurement, gene expression analysis Nature cardiovascular research High 35036997
2021 NAMPT-derived NAD+ fuels PARP1 hyperactivation in response to ROS-induced DNA damage, promoting parthanatos cell death and skin inflammation; genetic and pharmacological inhibition of NAMPT reduces oxidative stress, PARP1 activity, AIFM1 nuclear translocation, and keratinocyte hyperproliferation in zebrafish models and human 3D skin models of psoriasis. Zebrafish genetic/pharmacological inhibition models, human organotypic 3D skin models, PARP activity measurement, AIFM1 localization, gene expression analysis PLoS biology High 34748530
2021 STAT1 occupies a conserved intronic element (NRE1) within the Nampt gene in response to IFN-γ, driving NAMPT expression in macrophages; disruption of NRE1 reduces a subset of M1 inflammatory gene expression dependent on NAMPT-supported glycolysis, and myeloid-specific NRE1 ablation increases tumor burden in melanoma models. ChIP of STAT1 at NRE1, NRE1 knockout mouse strain, scRNAseq of tumor-associated leukocytes, pharmacological NAMPT inhibition, glycolysis assays Nature communications High 33976173
2022 miR-146a directly targets the 3'-UTR of Nampt mRNA to reduce NAMPT expression, thereby impairing AMPK-driven NAD+ synthesis and SIRT activity; AMPK activators (metformin, AICAR) suppress miR-146a transcription by promoting IKK phosphorylation and attenuating NF-κB activity, establishing a mutual inhibitory relationship between miR-146a and AMPK that regulates the NAD+/SIRT pathway. miR-146a overexpression/inhibition, 3'-UTR luciferase assay, NAMPT expression analysis, SIRT activity measurement, NF-κB/IKK assays, in vitro and in vivo experiments Signal transduction and targeted therapy High 35241643
2022 Lamin A/C deficiency causes reduced chromatin accessibility at the Nampt gene promoter (by ATAC-seq), leading to decreased NAMPT expression and reduced SIRT1 activity, which together impair NAD+ levels and mitochondrial function; high PARylation in lamin-aberrant cells further depletes the NAD+ pool. Lmna-/- MEFs, HGPS fibroblasts, ATAC-seq, NAD+ measurement, SIRT1 activity, mitochondrial DNA stability, bioenergetics assays Nucleic acids research High 36099415
2022 NAMPT depletion specifically in hippocampal CA1 neurons (via rAAV-Cre) causes cognitive deficiency, mitochondrial swelling and decreased mitochondrial number in neuronal cell bodies and neurites, increased intracellular Aβ aggregation, and gliosis; FK866 inhibition decreases neuronal NAD+, drops mitochondrial membrane potential, and reduces neuronal branching in a dose-dependent manner. rAAV-hSyn-Cre hippocampal CA1-specific Nampt KO, transmission electron microscopy, immunofluorescence, FK866 dose-response in primary neurons, mitochondrial membrane potential assay Molecular neurobiology High 36441480
2023 NAMPT activity is restored in aging by SIRT1 binding and subsequent deacetylation of NAMPT; low-dose nicotine activates this mechanism independently of nicotinic acetylcholine receptors, increasing NAD+ synthesis and ameliorating age-related metabolic and cognitive decline in mice. SIRT1-NAMPT co-immunoprecipitation, NAMPT deacetylation assay, 18F-FDG PET imaging, in vivo nicotine treatment of aging mice, cognitive and metabolic assays Nature communications High 36797299
2023 NAMPT-dependent NAD+ biosynthesis controls the molecular circadian clock in a tissue-specific manner: brown adipose tissue (BAT) requires NAMPT to sustain core clock amplitude and TCA cycle intermediate oscillations, white adipose tissue is moderately dependent, and skeletal muscle clock is completely refractory to NAMPT loss. Adipose-specific Nampt knockout mice, core clock gene expression, metabolomics, cold stress experiments Proceedings of the National Academy of Sciences of the United States of America High 36996103
2024 NAMPT deficiency in macrophages causes HIF-1α destabilization, leading to reduced M2-like tumor-associated macrophage (TAM) polarization and decreased efferocytosis; NAMPT deficiency also enhances STING signaling and type I IFN-response gene expression, potentiating cytotoxic T cell anti-tumor activity in colorectal cancer. Myeloid-specific Nampt knockout mice, scRNA-seq of tumor microenvironment, HIF-1α stability assay, efferocytosis assay, STING pathway analysis, T cell activity assays Advanced science High 38308188
2008 NAMPT/PBEF interacts with NADH dehydrogenase subunit 1 (ND1), ferritin light chain, and IFITM3 in human pulmonary vascular endothelial cells; PBEF overexpression increases these interactions and increases intracellular oxidative stress, attenuated by rotenone. Co-immunoprecipitation, overexpression, oxidative stress measurement, rotenone inhibition, interaction modeling FEBS letters Medium 18486613
2015 In hen granulosa cells, recombinant NAMPT (100 ng/ml) inhibits basal and IGF1-induced progesterone secretion by reducing STAR and HSD3B protein levels and MAPK3/1 phosphorylation; these effects are abolished by the NAMPT enzymatic inhibitor FK866, establishing that enzymatic activity is required for the reproductive effect. Recombinant NAMPT treatment, FK866 inhibition, western blotting for STAR/HSD3B, MAPK phosphorylation assay, progesterone RIA Reproduction (Cambridge, England) Medium 25918435
2019 NAMPT overexpression promotes cell survival under oxidative stress via both a SIRT1-dependent p53-CD38 pathway and a SIRT1-independent NRF2-PPARα/AMPKα pathway; NAMPT-activated NRF2 rescues mitochondrial membrane potential and content under H2O2 treatment, identifying NRF2 as a downstream target of NAMPT. NAMPT overexpression, H2O2 oxidative stress, SIRT1 inhibition, mitochondrial membrane potential assay, western blotting for NRF2/PPARα/AMPKα Cellular signalling Medium 31816398
2012 NAMPT activity regulates FOXO3a acetylation status and thereby controls GADD45A expression: increased intracellular NAD+ (via NAMPT) activates SIRT1 to deacetylate FOXO3a, reducing GADD45A transcription, while NAMPT inhibition leads to FOXO3a acetylation and GADD45A upregulation. NAMPT overexpression, FK866, SIRT1 shRNA, FOXO3a acetylation western blot, GADD45A expression analysis Biochemical and biophysical research communications Medium 22430142
2024 NAMPT deacetylation by SIRT2 activates LDHA, promoting lactate production through glycolysis in ovarian granulosa cells; FK866-mediated NAD+ synthesis inhibition increases LDHA acetylation (confirmed by Co-IP in 293T cells), reducing lactate and impairing follicular development in PCOS. Co-immunoprecipitation for LDHA acetylation, FK866 inhibition, NMN supplementation in PCOS rat model, transcriptomics, target energy metabolomics Free radical biology & medicine Medium 39489197

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
1994 Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Molecular and cellular biology 873 8289818
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2007 Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 810 17889652
2007 Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell metabolism 761 17983582
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. Journal of immunology (Baltimore, Md. : 1950) 738 17237424
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nature reviews. Endocrinology 577 26215259
2005 Plasma visfatin concentrations and fat depot-specific mRNA expression in humans. Diabetes 548 16186392
2006 Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 545 16496121
2005 Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus. The Journal of clinical endocrinology and metabolism 525 16234302
2004 Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. The Journal of clinical investigation 514 15124023
2002 Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. European journal of immunology 453 12555668
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2006 Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Annals of the rheumatic diseases 435 16414972
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2013 The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. The Journal of biological chemistry 413 23463506
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2008 Nampt: linking NAD biology, metabolism and cancer. Trends in endocrinology and metabolism: TEM 337 19109034
2019 Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice. Cell metabolism 326 31204283
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2007 Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. The Journal of biological chemistry 271 17307730
2007 The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Current opinion in gastroenterology 251 17268245
2006 Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nature structural & molecular biology 246 16783373
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