Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin is required for lymphocyte development and cellular resistance to genotoxic stress.
Nicotinamide phosphoribosyl transferase (Nampt)/pre-B cell colony-enhancing factor (PBEF)/visfatin is a protein displaying multiple functional properties. Originally described as a cytokine-like protein able to regulate B cell development, apoptosis, and glucose metabolism, this protein also plays an important role in NAD biosynthesis. To gain insight into its physiological role, we have generated a mouse strain expressing a conditional Nampt allele. Lack of Nampt expression strongly affects development of both T and B lymphocytes. Analysis of hemizygous cells and in vitro cell lines expressing distinct levels of Nampt illustrates the critical role of this protein in regulating intracellular NAD levels. Consequently, a clear relationship was found between intracellular Nampt levels and cell death in response to the genotoxic agent MNNG (N-methyl-N'-nitro-N-nitrosoguanidine), confirming that this enzyme represents a key regulator of cell sensitivity to NAD-consuming stress secondary to poly(ADP-ribose) polymerases overactivation. By using mutant forms of this protein and a well-characterized pharmacological inhibitor (FK866), we unequivocally demonstrate that the ability of the Nampt to regulate cell viability during genotoxic stress requires its enzymatic activity. Collectively, these data demonstrate that Nampt participates in cellular resistance to genotoxic/oxidative stress, and it may confer to cells of the immune system the ability to survive during stressful situations such as inflammation.
Rongvaux
Anthony
A
Laboratoire de Physiologie Animale, Institut de Biologie et Médecine Moléculaire (IBMM), Université Libre de Bruxelles, Gosselies, Belgium.
Galli
Mara
M
Denanglaire
Sébastien
S
Van Gool
Frédéric
F
Drèze
Pierre L
PL
Szpirer
Claude
C
Bureau
Fabrice
F
Andris
Fabienne
F
Leo
Oberdan
O
D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D054409:Nicotinamide Phosphoribosyltransferase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D008769:Methylnitronitrosoguanidine; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse