Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA

Rongvaux, Anthony; Jackson, Ruaidhrí; Harman, Christian C. D.; Li, Tuo; West, A. Phillip; Zoete, Marcel R. de; Wu, Ya Fei; Yordy, Brian; Lakhani, Saquib A.; Kuan, Chia Yi; Taniguchi, Tadatsugu; Shadel, Gerald S.; Chen, Zhijian J.; Iwasaki, Akiko; Flavell, Richard A.

doi:10.1016/j.cell.2014.11.037

Cited by 635 publications

(621 citation statements)

References 56 publications

(74 reference statements)

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“…This finding underlines the interferogenic characteristics of mtDNA previously reported by others (5,6,24). Notably, mtDNA is recognized by more than one immune signaling pathway.…”

Section: Discussionsupporting

confidence: 75%

“…Released mtDNA participates in inflammatory responses via different pathways. In the cGAS/STING pathway, mtDNA participates in cell-intrinsic triggering of innate immune responses and antiviral signaling, and trigger type I interferon (IFN) release (4)(5)(6). Similar to bacterial and viral DNA, mtDNA is enriched in unmethylated CpG dinucleotide motifs, which exhibit strong immunostimulatory effects (7).…”

Section: Introductionmentioning

confidence: 99%

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Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C

Ingelsson

Söderberg

Strid

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

108

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Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

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“…This finding underlines the interferogenic characteristics of mtDNA previously reported by others (5,6,24). Notably, mtDNA is recognized by more than one immune signaling pathway.…”

Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C

Ingelsson

Söderberg

Strid

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Indeed, (i) a number of off-targeting effects interfering with necroptosis were reported for caspases inibitors. 51,52 (ii) In addition to masking the potential role of the NAD + -sirtuin axis, recent observations indicate that these inhibitors can promote the production of soluble factors, including a number of cytokines (IL-6, IL-1β, IL-8, GM-CSF and CXCL2), chemokines (CCL2, RANTES and CXCL1) 53 and type I interferons (in response to mitochondrial damage) 54,55 that could interfere with the necroptotic signaling pathway. [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.…”

Section: Discussionmentioning

confidence: 99%

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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“…Nevertheless, inhibition of caspase function may have untoward and potentially unwanted effects. For example, MOMP in the absence of caspase activity can engage interferon responses dependent upon activation of the STING pathway 121,122 . The role of STINGdependent interferon signaling in cancer is complex such that it can exert both pro-and anti-tumourigenic effects 123,124 .…”

Section: Targeting Apoptosis -Pushing Over the Edge And Pulling Backmentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA

Cited by 635 publications

References 56 publications

Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C

Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C

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

A fate worse than death: apoptosis as an oncogenic process

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