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Nicotinamide Phosphoribosyl Transferase/Pre-B Cell Colony-Enhancing Factor/Visfatin Is Required for Lymphocyte Development and Cellular Resistance to Genotoxic Stress¹

Anthony Rongvaux^2,*, Mara Galli^2,*, Sébastien Denanglaire^*, Frédéric Van Gool^*, Pierre L. Drèze, Claude Szpirer, Fabrice Bureau, Fabienne Andris^* and Oberdan Leo^3,*

^* Laboratoire de Physiologie Animale and Laboratoire de Biologie du Développement, Institut de Biologie et Médecine Moléculaire (IBMM), Université Libre de Bruxelles, Gosselies, Belgium; and Laboratoire de Physiologie, Faculté de Médecine Vétérinaire, Centre de Thérapie Cellulaire et Moléculaire, Université de Liége, Belgium

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Belgian Program in Interuniversity Poles of Attraction Initiated by the Belgian Sate, Prime Minister’s office, Science Policy Programming, by a Research Concerted Action of the Communauté Française de Belgique and by a grant from the "Fonds Jean Brachet". This work was also supported by the "Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture" (FRIA) and the National Fund for Scientific Research (FNRS), Belgium. F.A. is a Research Associate and C.S. a Research Director of the the FNRS, Belgium.

² A.R. and M.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Oberdan Leo, Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Institut de Biologie et de Médecine Moléculaires, 12, rue des Professeur Jeener et Brachet, 6041 Gosselies, Belgium. E-mail address: oleo{at}ulb.ac.be

⁴ Abbreviations used in this paper: Nampt, nicotinamide phosphoribosyltranferase; AIF, apoptosis-inducing factor; eGFP, enhanced GFP; ES cell, embryonic stem cell; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; MSCV, murine stem cell virus; Napt, nicotinic acid phosphoribosyltranferase; PARP, poly(ADP-ribose) polymerase; PBEF, pre-B cell colony-enhancing factor; Rpl32, ribosomal protein L32; shRNA, short hairpin RNA; TDO, tryptophan 2,3-dioxygenase; wt, wild type.

⁵ The online version of this article contains supplemental material.

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