Sirtuin deacylases: a molecular link between metabolism and immunity

Preyat, Nicolas; Léo, Oberdan

doi:10.1189/jlb.1112557

Cited by 119 publications

(97 citation statements)

References 150 publications

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“…Both SIRT2 and SIRT5 appeared to affect the stability of RIPK1-RIPK3 association. Whether these two sirtuins share the same substrate (as previously described and discussed for other sirtuins pairs) 49 and/or affect distinct substrates involved in necrosome assembly is presently unknown and under investigation. The present work may help to shed some light on the controversial issue surrounding the role of sirtuins in necroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…[56][57][58] Although the present study confirms previously reported observations suggesting a role for SIRT2 in promoting necroptosis, 33 they are at apparent odds with the observation that SIRT2-KO mice remain sensitive to the in vivo toxicity of exogenously administered TNF. 50 Possible explanations for this apparent discrepancy include the possible functional redundancy between sirtuin members as this multigene family often share substrate specificity 49 and the uncertainty concerning the mechanism underlying TNF toxicity in SIRT2-KO mice. 50 Also of relevance are the observations that, quite often, inhibition of sirtuin activity can promote an alternative form of cell death (see Figure 2d and Supplementary Figure S3b), warranting further investigations in the mode of cell death induced by TNF in SIRT2-KO mice.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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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. + as a substrate in a number of regulatory processes has shed a new light on its role in cell physiology. Indeed, NAD + represents a substrate for a wide range of enzymes including cADP-ribose synthases, poly (ADP-ribose) polymerases (PARPs) and the sirtuin family of NAD + -dependent deacylases (SIRTs). In marked contrast to its role in energy metabolism, the involvement of NAD + in these enzymatic reactions is based on its ability to function as a donor of ADP-ribose, a reaction that, if sustained, can lead to the depletion of the intracellular NAD + pool. 1-5The pro-survival role of NAD + has been particularly well described in cells exposed to genotoxic/oxidative stress. In response to DNA damage, PARP1, the founding and most abundant member of the PARP family, binds to DNA strand breaks and initiates a repair response by catalyzing the posttranslational modification of several nuclear proteins, including itself. This protective response is characterized by the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD + to other proteins, compromising therefore both energy production (slowing the rate of glycolysis, electron transport and ATP formation) and activity of other NAD + -dependent enzymes through NAD + depletion. 6,7 Moreover, PARP1-synthesized PAR polymers can be degraded into free oligomers, known to translocate to the mitochondria where they can trigger the release of AIF from mitochondria to the nucleus. [8][9][10][11] The precise molecular steps linking PARP1 activation to this form of stress-induced cell death, termed parthanatos, have not been fully elucidated, and...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

et al. 2015

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“…They have been implicated in diverse biological events, such as aging, energy control, circadian clocks, and mitochondrial biogenesis (Baur, Ungvari, Minor, Le Couteur, & de Cabo, 2012; Preyat & Leo, 2013; Wood et al., 2004). Of them, Sirt2 is associated with mitotic structures, beginning with the centrosome in mitotic prophase, the spindle in metaphase, and the midbody during cytokinesis, presumably to ensure normal cell division (North & Verdin, 2007).…”

Section: Introductionmentioning

confidence: 99%

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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SummaryThe level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age‐associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore–microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1‐K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation‐mimetic mutant BubR1‐K243Q results in the very similar phenotypes as Sirt2‐knockdown oocytes. Furthermore, we found that nonacetylatable‐mimetic mutant BubR1‐K243R partly prevents the meiotic deficits in oocytes depleted of Sirt2. Importantly, BubR1‐K243R overexpression in oocytes derived from aged mice markedly suppresses spindle/chromosome anomalies and thereupon lowers the incidence of aneuploid eggs. In sum, our data suggest that Sirt2‐dependent BubR1 deacetylation involves in the regulation of meiotic apparatus in normal oocytes and mediates the effects of advanced maternal age on oocyte quality.

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“…SIRT6 also plays a role in inflammatory pathways, exerting anti-inflammatory effects at the transcriptional level. However, other studies suggest a pro-inflammatory effect on intracellular signaling (6). Although it is clear that SIRT6 functions in metabolism, inflammation, and genome maintenance, its molecular functions remain enigmatic.…”

mentioning

confidence: 97%

Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins

Feldman

Baeza

Denu

2013

Journal of Biological Chemistry

562

682

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Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.

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Sirtuin deacylases: a molecular link between metabolism and immunity

Cited by 119 publications

References 150 publications

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins

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