Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 11, Pages 3635-3651Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.010571
Keywords
NAD biosynthesis; NAMPT; melanoma; nicotinamide adenine dinucleotide (NAD); metabolism; GAPDH; NAD compartmentalization; nucleus; nicotinamide mononucleotide (NMN); protein-protein interaction; cell stress; redox cycling; NMN; NAD plus salvage pathway
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Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG2018 21842]
- PRIN 2017 CBNCYT from the Italian Ministry of Health
- Fondazione Umberto Veronesi Grant 2018
- SIF-Merck scholarship
- Universita del Piemonte Orientale Grant FAR 2015
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All cells require sustained intracellular energy flux, which is driven by redox chemistry at the subcellular level. NAD(+), its phosphorylated variant NAD(P)(+), and its reduced forms NAD(P)/NAD(P)H are all redox cofactors with key roles in energy metabolism and are substrates for several NAD-consuming enzymes (e.g. poly(ADP-ribose) polymerases, sirtuins, and others). The nicotinamide salvage pathway, constituted by nicotinamide mononucleotide adenylyltransferase (NMNAT) and nicotinamide phosphoribosyltransferase (NAMPT), mainly replenishes NAD(+) in eukaryotes. However, unlike NMNAT1, NAMPT is not known to be a nuclear protein, prompting the question of how the nuclear NAD(+) pool is maintained and how it is replenished upon NAD(+) consumption. In the present work, using human and murine cells; immunoprecipitation, pulldown, and surface plasmon resonance assays; and immunofluorescence, small-angle X-ray scattering, and MS-based analyses, we report that GAPDH and NAMPT form a stable complex that is essential for nuclear translocation of NAMPT. This translocation furnishes NMN to replenish NAD(+) to compensate for the activation of NAD-consuming enzymes by stressful stimuli induced by exposure to H2O2 or S-nitrosoglutathione and DNA damage inducers. These results indicate that by forming a complex with GAPDH, NAMPT can translocate to the nucleus and thereby sustain the stress-induced NMN/NAD(+) salvage pathway.
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