scholarly journals NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001455
Author(s):  
Francisco J. Martínez-Morcillo ◽  
Joaquín Cantón-Sandoval ◽  
Francisco J. Martínez-Navarro ◽  
Isabel Cabas ◽  
Idoya Martínez-Vicente ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Nuclear Translocation ◽  
Skin Inflammation ◽  
Ros Scavenging ◽  
Nadph Oxidases ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Pharmacological Inhibition ◽  
Chronic Skin ◽  
Apoptosis Inducing Factor

Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.

scholarly journals NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos

2021 ◽  
Author(s):  
Francisco J. Martínez-Morcillo ◽  
Joaquín Cantón-Sandoval ◽  
Francisco J. Martínez-Navarro ◽  
Isabel Cabas ◽  
Idoya Martínez-Vicente ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Skin Inflammation ◽  
List Type ◽  
Ros Scavenging ◽  
Nadph Oxidases ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Pharmacological Inhibition ◽  
Chronic Skin ◽  
Apoptosis Inducing Factor

SummarySeveral studies have revealed a correlation between chronic inflammation and NAD+ metabolism but the precise mechanism involved is unknown. Here we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly ADP-ribose (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases and reactive oxygen species (ROS) scavenging, all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of both NAMPT amounts and PARP activity was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.HighlightsNAMPT inhibition alleviates inflammation in zebrafish and human epidermis organoid models of psoriasis.NADPH oxidase-derived ROS mediates keratinocyte DNA damage and Parp1 overactivation.Inhibition of parthanatos cell death phenocopies the effects of NAMPT inhibition in zebrafish and human psoriasis models.NAMPT and PAR metabolism is altered in psoriasis patients.

scholarly journals DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lama Tarayrah-Ibraheim ◽  
Elital Chass Maurice ◽  
Guy Hadary ◽  
Sharon Ben-Hur ◽  
Alina Kolpakova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Germ Cells ◽  
Nuclear Translocation ◽  
Primordial Germ Cells ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Dnase Ii ◽  
Cell Death Pathway ◽  
Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

scholarly journals Nuclear Translocation of Apoptosis-Inducing Factor after Focal Cerebral Ischemia

2004 ◽  
Vol 24 (4) ◽  
pp. 458-466 ◽  
Author(s):  
Nikolaus Plesnila ◽  
Changlian Zhu ◽  
Carsten Culmsee ◽  
Moritz Gröger ◽  
Michael A. Moskowitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Cytochrome C ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Mitochondrial Protein ◽  
Neuronal Cell ◽  
Experimental Stroke ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Signaling cascades associated with apoptosis contribute to cell death after focal cerebral ischemia. Cytochrome c release from mitochondria and the subsequent activation of caspases 9 and 3 are critical steps. Recently, a novel mitochondrial protein, apoptosis-inducing factor (AIF), has been implicated in caspase-independent programmed cell death following its translocation to the nucleus. We, therefore, addressed the question whether AIF also plays a role in cell death after focal cerebral ischemia. We detected AIF relocation from mitochondria to nucleus in primary cultured rat neurons 4 and 8 hours after 4 hours of oxygen/glucose deprivation. In ischemic mouse brain, AIF was detected within the nucleus 1 hour after reperfusion after 45 minutes occlusion of the middle cerebral artery. AIF translocation preceded cell death, occurred before or at the time when cytochrome c was released from mitochondria, and was evident within cells showing apoptosis-related DNA fragmentation. From these findings, we infer that AIF may be involved in neuronal cell death after focal cerebral ischemia and that caspase-independent signaling pathways downstream of mitochondria may play a role in apoptotic-like cell death after experimental stroke.

scholarly journals Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy

2021 ◽  
Vol 13 (581) ◽  
pp. eabf0891 ◽  
Author(s):  
Stephen P. Chelko ◽  
Gizem Keceli ◽  
Andrea Carpi ◽  
Nunzianna Doti ◽  
Jacopo Agrimi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Large Scale ◽  
Nuclear Translocation ◽  
Myocardial Dysfunction ◽  
Embryonic Stem ◽  
Redox System ◽  
Adrenergic Stimulation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Apoptosis Inducing Factor

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload–induced necrosis. When cardiomyocytes differentiated from Dsg2mut/mut embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.

scholarly journals Endonuclease G does not play an obligatory role in poly(ADP-ribose) polymerase-dependent cell death after transient focal cerebral ischemia

2010 ◽  
Vol 299 (1) ◽  
pp. R215-R221 ◽  
Author(s):  
Zhenfeng Xu ◽  
Jian Zhang ◽  
Karen K. David ◽  
Zeng-Jin Yang ◽  
Xiaoling Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Wild Type ◽  
Endonuclease G ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Inducing Factor

Activation of poly(ADP-ribose) polymerase (PARP) and subsequent translocation of apoptosis-inducing factor contribute to caspase-independent neuronal injury from N-methyl-d-aspartate, oxygen-glucose deprivation, and ischemic stroke. Some studies have implicated endonuclease G in the DNA fragmentation associated with caspase-independent cell death. Here, we compared wild-type and endonuclease G null mice to investigate whether endonuclease G plays a role in the PARP-dependent injury that results from transient focal cerebral ischemia. Latex casts did not reveal differences in the cerebral arterial distribution territory or posterior communicating arterial diameter, and the decrease in laser-Doppler flux during middle cerebral artery occlusion was similar in wild-type and endonuclease G null mice. After 90 min of occlusion and 1 day of reperfusion, similar degrees of nuclear translocation of apoptosis-inducing factor and DNA degradation were evident in male wild-type and null mice. At 3 days of reperfusion, infarct volume and neurological deficit scores were not different between male wild-type and endonuclease G null mice or between female wild-type and endonuclease G null mice. These data demonstrate that endonuclease G is not required for the pathogenesis of transient focal ischemia in either male or female mice. Treatment with a PARP inhibitor decreased infarct volume and deficit scores equivalently in male wild-type and endonuclease G null mice, indicating that the injury in endonuclease G null mice remains dependent on PARP. Thus endonuclease G is not obligatory for executing PARP-dependent injury during ischemic stroke.

scholarly journals GSTpi reduces DNA damage and cell death by regulating the ubiquitination and nuclear translocation of NBS1

2021 ◽  
Author(s):  
Jinyi Zhou ◽  
Lili Gu ◽  
Yingying Shi ◽  
Ting Huang ◽  
Xirui Fan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Nuclear Translocation
Sign in / Sign up

Export Citation Format

Share Document