title: Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner.
abstract: Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors.
authors.affiliation: Laboratory of Immunobiology, Institute for Molecular Biology and Medicine, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Preyat
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kers
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Le Moine
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rongvaux
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Van Gool
authors.affiliation: Laboratory of Immunobiology, Institute for Molecular Biology and Medicine, Université Libre de Bruxelles, Gosselies, Belgium.|Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: Leo
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis / Q000235:genetics* / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C474199:SIRT2 protein, human; C508544:SIRT5 protein, human; D056565:Sirtuin 2; D037761:Sirtuins