Nicotinamide adenine dinucleotide (NAD+) represents a long-known key molecule in cellular metabolism. It was initially identified for its ability to convey electrons and protons between redox partners in multiple bioenergetic and biosynthetic reactions. In addition, NAD+ also serves as a substrate for NAD+-consuming enzymes such as sirtuins and poly ADP-ribose polymerases (PARPs). These latter enzymes catalyze dynamic post-translational modifications that control virtually every signaling pathway orchestrating cell fate. The aim of this work was to analyze the role of NAD+ in the context of programmed cell death mechanisms.<p>Our findings indicate that NAD+ is protective against DNA damage-induced cell death and FAS-induced apoptosis, while, unexpectedly, it promotes TNF-induced necroptosis, a regulated form of necrosis. Indeed raising NAD+ cellular levels sensitized culture cells to necroptosis, while NAD+ depletion protected cells from this form of cell death. Furthermore, specific silencing of NAD+-dependent sirtuins was also found to be protective against TNF-induced necroptosis. Consistently, a pharmacological pan-sirtuin inhibitor called cambinol protected cells from necroptosis. Then, as necroptosis represents a back-up mechanism that may have evolved in response to viral pathogens expressing anti-apoptotic proteins, we demonstrated in an in vitro model mimicking viral infection that pharmacological sirtuin inhibition protected cells from poly I:C-induced necroptotic cell death. In vivo, we demonstrated that cambinol partially protected kidney from necrosis after ischemia/reperfusion. We have also shown that enhancing liver NAD+ concentration via isonicotinamide increases the susceptibility of mice to systemic inflammatory response syndrome (SIRS). Moreover, our preliminary data show that isonicotinamide substantially improves the ability of cyclophosphamide to trigger the rejection of the murine mastocytoma P815 tumor cell line.<p>Collectively, our observations point to a role for NAD+ in the control of necroptosis in a sirtuin-dependent manner. These observations may bear relevance to the better understanding of the pathophysiological consequences of excessive production of the pro-inflammatory cytokine TNF and the control of viral infections and tumor progression/immunotherapy. & / Doctorat en Sciences / info:eu-repo/semantics/nonPublished
| Identifer | oai:union.ndltd.org:ulb.ac.be/oai:dipot.ulb.ac.be:2013/209470 |
| Date | 28 June 2013 |
| Creators | Preyat, Nicolas |
| Contributors | Leo, Oberdan, Pays, Etienne, Marini, Anna Maria, Kruys, Véronique, Van hamme, Luc, Gueydan, Cyril, Moser, Muriel, Vandenabeele, Peter |
| Publisher | Universite Libre de Bruxelles, Université libre de Bruxelles, Faculté des Sciences – Sciences biologiques, Bruxelles |
| Source Sets | Université libre de Bruxelles |
| Language | French |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:ulb-repo/semantics/doctoralThesis, info:ulb-repo/semantics/openurl/vlink-dissertation |
| Format | 1 v. (109, xxvi p.), No full-text files |
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