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| Open AccessThe NMDA receptor regulates competition of epithelial cells in the Drosophila wing
Cell competition among epithelial cells allows removal of unfit or dangerous cells. Here, the authors show that the NMDA receptor is an important determinant of cell fitness in the Drosophila wing, also in the context of Myc super-competitor cells, with “loser” cells contributing metabolitic fuel to “winner” cells.
- Agnes R. Banreti
- & Pascal Meier
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Article
| Open AccessN-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
- Mausita Karmakar
- , Martin Minns
- & Eric Pearlman
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| Open AccessZika virus noncoding RNA suppresses apoptosis and is required for virus transmission by mosquitoes
The function on subgenomic flaviviral RNA (sfRNA) in the mosquito vector is not well understood. Here, Slonchak et al. show that sfRNA affects virus-induced apoptosis and dissemination of ZIKV in Aedes aegypti mosquitoes, suggesting a role of sfRNA in Zika virus replication and transmission.
- Andrii Slonchak
- , Leon E. Hugo
- & Alexander A. Khromykh
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| Open AccessTargeting codon 158 p53-mutant cancers via the induction of p53 acetylation
Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer. Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-ĸB signaling.
- Li Ren Kong
- , Richard Weijie Ong
- & Boon Cher Goh
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Article
| Open AccessAging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction
Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA Sarrah, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.
- D. Julia Trembinski
- , Diewertje I. Bink
- & Reinier A. Boon
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Article
| Open AccessAutophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation
Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses. Here the authors show that autophosphorylation at Ser166 is required for RIPK1-mediated cell death and inflammation in mouse models of inflammatory pathologies, making Ser166 phosphorylation a possible biomarker for RIPK1-mediated inflammatory diseases.
- Lucie Laurien
- , Masahiro Nagata
- & Manolis Pasparakis
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Article
| Open AccessDJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase
DJ-1 protects cells from oxidative stress-induced cell death; however its role in ferroptosis is unclear. Here, the authors show that DJ-1 suppresses ferroptosis through the transsulfuration pathway to compensate for the depletion of intracellular cysteine when cystine import is inhibited.
- Ji Cao
- , Xiaobing Chen
- & Meidan Ying
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Article
| Open AccessYAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
The precise mechanisms of neuronal cell death in neurodegeneration are not fully understood. Here the authors show that YAP-mediated neuronal necrosis is increased in pre-symptomatic stages of Alzheimer’s disease and intervention to the necrosis rescues extracellular Aβ aggregation and symptoms in a mouse model.
- Hikari Tanaka
- , Hidenori Homma
- & Hitoshi Okazawa
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Article
| Open AccessDisruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis
Acid-sensing ion channel 1a (ASIC1a) mediates acidic neuronal necroptosis via recruiting receptor-interacting protein kinase 1 (RIPK1). Here authors show that auto-inhibition of ASICa prevents RIPK1 recruitment and demonstrate that targeting the auto-inhibition has therapeutic potential to prevent acidotoxicity.
- Jing-Jing Wang
- , Fan Liu
- & Tian-Le Xu
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Article
| Open AccessNedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma
Erastin, the ferroptosis activator, binds to voltage gated ion channels CDAC2 and VDCA3 but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels.
- Yongfei Yang
- , Meiying Luo
- & Wei Chen
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Article
| Open AccessSTING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment
Antimitotic compounds, such as paclitaxel, induce cell death in cycling cancer cells only. Here, the authors show that paclitaxel-targeted breast cancer cells prime neighboring cells to apoptosis through a STING-mediated paracrine signaling pathway.
- Steven Lohard
- , Nathalie Bourgeois
- & Sophie Barillé-Nion
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Article
| Open AccessTargeting of apoptosis gene loci by reprogramming factors leads to selective eradication of leukemia cells
Yamanaka factors can reprogram somatic and cancer cells into induced pluripotent stem cells. Here, the authors show that the induction of these factors in acute myeloid leukemia leads to apoptosis of leukemia cells in vivo, and this is through modulation of chromatin accessibility to apoptotic genes and accompanied by H3K9me3 dysregulation.
- Yajie Wang
- , Ting Lu
- & Tao Cheng
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Article
| Open AccessGenome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer
Gemcitabine is used to treat gallbaldder cancer but patient responses are variable. Here, the authors use a genome-wide CRISPR screen and identify the translational elongator protein ELP5 as a protein that is important for mediating gemcitabine-induced apoptosis.
- Sunwang Xu
- , Ming Zhan
- & Jian Wang
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| Open AccessTargeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors
BRAF or MEK1/2 inhibitors are cytostatic in melanoma and the surviving cells develop drug resistance. This study shows that the pro-survival pool is biased towards MCL1 in melanoma so that BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, improving tumour growth inhibition.
- Matthew J. Sale
- , Emma Minihane
- & Simon J. Cook
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Article
| Open AccessRecurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma
Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive disease. Here, the authors identify recurrent somatic mutations of GNAQ in NKTCL, and model how this mutation contributes to NKTCL pathogenesis.
- Zhaoming Li
- , Xudong Zhang
- & Mingzhi Zhang
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Article
| Open AccessUbiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis
RIPK1 integrates signals that drive both NF-κB activation and cell death pathways. Here Zhang et al. generate RIPK1 knock-in mice lacking a major ubiquitination site and demonstrate that this modification is important to suppress cell death during embryogenesis and inflammation postnatally.
- Xixi Zhang
- , Haiwei Zhang
- & Haibing Zhang
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Article
| Open AccessIdentification of intracellular cavin target proteins reveals cavin-PP1alpha interactions regulate apoptosis
Caveolae are plasma membrane invaginations containing cavin proteins that are disrupted upon stress stimuli, causing cavin release inside the cell. Here, McMahon et al. identify cavin interacting proteins using proteomic analyses and reveal functions in stress signaling that can promote apoptosis.
- Kerrie-Ann McMahon
- , Yeping Wu
- & Robert G. Parton
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Article
| Open AccessPRKCSH contributes to tumorigenesis by selective boosting of IRE1 signaling pathway
Cancer cells utilise the unfolded protein response (UPR) to adapt to environmental and ER stress. Here, the authors show that the glycosidase II beta subunit, PRKSCH, protects cancer cells from ER stress, by interacting with IRE1α and activating the IRE1α-XBP1 branch of the UPR.
- Gu-Choul Shin
- , Sung Ung Moon
- & Kyun-Hwan Kim
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Article
| Open AccessInvolvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis
Altered iron homeostasis resulting in excessive oxidative stress has been implicated in smoke-induced lung diseases. Here the authors show that ferroptosis of lung epithelial cells, potentially resulting from excessive ferritinophagy, is involved in the pathogenesis of COPD.
- Masahiro Yoshida
- , Shunsuke Minagawa
- & Kazuyoshi Kuwano
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| Open AccessApoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95
Fas is a death receptor that regulates apoptosis in many cell types and is downregulated on the cell surface in many cancers. Here, Sharma et al. show that endosome associated trafficking regulator ENTR1 regulates delivery of Fas to lysosomes, thereby controlling its degradation and signalling.
- Shruti Sharma
- , Antonio Carmona
- & Kai S. Erdmann
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| Open AccessExploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Senescence induction is known to induce stable proliferation arrest. Here, the authors show that sustained PARP inhibition promotes a reversible p53-independent senescence, and that PARP inhibition is synthetic lethal when combined with senolytic agents in pre-clinical models of ovarian and breast cancer.
- Hubert Fleury
- , Nicolas Malaquin
- & Francis Rodier
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Article
| Open AccessCaspase-1 initiates apoptosis in the absence of gasdermin D
In inflammasomes, caspase-1 activation leads to pyroptosis mediated by gasdermin D, but cells lacking gasdermin-D still initiate caspase-dependent cell death. Here, Tsuchiya et al. show that these cells undergo Bid- and caspase-3-dependent apoptosis.
- Kohsuke Tsuchiya
- , Shinsuke Nakajima
- & Takashi Suda
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Article
| Open AccessMolecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote
Box jellyfish venom causes tissue damage, pain, and death through unknown molecular mechanisms. Here, Lau et al. perform a CRISPR screen to identify genes required for venom action and use this information to develop an antidote that blocks venom-induced pain and tissue damage in vivo.
- Man-Tat Lau
- , John Manion
- & G. Gregory Neely
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Article
| Open AccessA conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
Cerebral Cavernous Malformations (CCM) are often caused by mutations in CCM1/KRIT1. Here, Chapman et al. elegantly show that the CCM complex promotes apoptosis by regulating zinc homeostasis and storage via a conserved mechanism that likely generates the pathological defects observed in CCM.
- Eric M. Chapman
- , Benjamin Lant
- & W. Brent Derry
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Article
| Open AccessSerine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.
- Yves Dondelinger
- , Tom Delanghe
- & Mathieu J. M. Bertrand
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| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessMultimodal interference-based imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm
Methods to track molecular motion in eukaryotic cells mostly rely on fluorescent labels, transfection or photobleaching. Here the authors use multimodal partial wave spectroscopy to perform label-free live cell measurements of nanoscale structure and macromolecular motion with millisecond temporal resolution.
- Scott Gladstein
- , Luay M. Almassalha
- & Vadim Backman
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| Open AccessA GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids.
- Yilong Zou
- , Michael J. Palte
- & Stuart L. Schreiber
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Article
| Open AccessCrizotinib-induced immunogenic cell death in non-small cell lung cancer
Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.
- Peng Liu
- , Liwei Zhao
- & Guido Kroemer
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Article
| Open AccessTargeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma
Dermal myofibroblasts are responsible for fibrosis development in scleroderma. Here the authors show that a bioengineered recombinant human TRAIL ligand reverses established fibrosis in mouse models of scleroderma by targeting the death receptor 5 and inducing apoptosis of myofibroblasts.
- Jong-Sung Park
- , Yumin Oh
- & Seulki Lee
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| Open AccessStem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance
Damaged epithelial tissues are known to compensate for cell death through compensatory cell divisions to maintain epithelial integrity. Here, the authors show in living epithelia that dying cells stimulate adjacent stem cells to divide through caspase-dependent production of Wnt8a-containing apoptotic bodies.
- Courtney K. Brock
- , Stephen T. Wallin
- & George T. Eisenhoffer
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| Open AccessThe Caspase-3 homolog DrICE regulates endocytic trafficking during Drosophila tracheal morphogenesis
Caspases are well-known drivers of apoptosis, although recent studies suggest potential non-apoptotic functions. Here, McSharry and Beitel show that the Drosophila executioner caspase DrICE regulates endocytic trafficking of key proteins downstream of Hippo during tracheal morphogenesis.
- Saoirse S. McSharry
- & Greg J. Beitel
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Article
| Open AccessPlasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Neutrophil extracellular traps (NETs) are known to promote metastasis in mouse models. Here the authors show plasma redox imbalance caused by albumin oxidation to induce inflammation-independent NETosis and lung metastasis, and albumin oxidation and reduced plasma free thiol to be associated with lung metastasis in a cohort of head and neck cancer patients.
- Minoru Inoue
- , Ryota Nakashima
- & Scott V. Bratman
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Article
| Open AccessVDAC2 enables BAX to mediate apoptosis and limit tumor development
BAX and BAK are pro-apoptotic proteins whose activity is essential for the action of many anti-cancer drugs and to suppress tumorigenesis. Here, the authors perform a genome-wide CRISPR/Cas9 screen and identify VDAC2 as a promoter of BAX-mediated apoptosis that is important for an efficient chemotherapeutic response and to suppress tumor formation.
- Hui San Chin
- , Mark X. Li
- & Grant Dewson
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Article
| Open AccessARTS mediates apoptosis and regeneration of the intestinal stem cell niche
The mechanisms regulating intestinal stem cell elimination remain unclear. Here, the authors identify that the pro-apoptotic protein ARTS (a Septin4 isoform) interacts with XIAP in the intestinal stem cell niche to regulate stem cell survival during intestinal homeostasis and regeneration.
- Elle Koren
- , Yahav Yosefzon
- & Yaron Fuchs
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Article
| Open AccessA FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs
Necroptotic cells activate MLKL and release inflammatory DAMPs, although the underlying regulatory mechanisms of this process are poorly understood. Here, Murai et al. develop a necroptosis-specific FRET sensor (SMART) that monitors MLKL membrane translocation to identify two modes of DAMP release.
- Shin Murai
- , Yoshifumi Yamaguchi
- & Hiroyasu Nakano
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Article
| Open AccessLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
- Lucia Taraborrelli
- , Nieves Peltzer
- & Henning Walczak
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Article
| Open AccessChromatin swelling drives neutrophil extracellular trap release
Neutrophilic granulocytes release their own DNA (NETosis) as neutrophil extracellular traps to capture pathogens. Here, the authors use time-resolved fluorescence and atomic force microscopy and reveal that NETosis is highly organized into three distinct phases with a clear point of no return defined by chromatin status.
- Elsa Neubert
- , Daniel Meyer
- & Sebastian Kruss
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Article
| Open AccessNecroptosis mediates myofibre death in dystrophin-deficient mice
Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration.
- Jennifer E. Morgan
- , Alexandre Prola
- & Maximilien Bencze
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Article
| Open AccessIdentification of a novel anoikis signalling pathway using the fungal virulence factor gliotoxin
Gliotoxin (GT), produced by the pulmonary pathogen A. fumigatus, induces detachment-induced apoptosis (anoikis) of lung epithelial cells and likely promotes invasion. Here, the authors show that GT covalently modifies integrins at the RGD binding site followed by activation of RhoA-ROCK-MKK4/7-JNK signalling leading to Bim-mediated anoikis.
- Florian Haun
- , Simon Neumann
- & Christoph Borner
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Article
| Open AccessSystematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity
Dependency of diverse cancers on specific BCL-2 family members and their combinations is unknown. Here they perform drug screening and find most cell lines to be dependent on at least one combination of BCL-2 family members, and using a CRISPR screen find BCL-w and BFL-1 to mediate resistance to BH3 mimetics
- Ryan S. Soderquist
- , Lorin Crawford
- & Kris C. Wood
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Article
| Open AccessP38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim
Erythropoietin (EPO) stimulates erythropoiesis and is commonly used to treat anemia. Here Hu et al. find that P38α/JNK signaling restrains erythropoiesis independently of EPO by regulating epigenetic silencing of the proapoptotic protein Bim, and thus identify putative targets for the treatment of anemic disorders resistant to EPO.
- Ping Hu
- , Angel R. Nebreda
- & Reuben Kapur
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Article
| Open AccessThe cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function
Mitochondrial cristae shape influences apoptosis and respiration. Here the authors show that the mitochondrial fusion protein OPA1 protects mitochondria from dysfunction by promoting ATP synthase oligomerization and reversal activity.
- Rubén Quintana-Cabrera
- , Charlotte Quirin
- & Luca Scorrano
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Article
| Open AccessSUMO-mediated regulation of NLRP3 modulates inflammasome activity
The NLRP3 inflammasome is an important component of inflammatory responses, but how it is negatively regulated is still unclear. Here the authors show that post-translational modification of NLRP3 by sumoylation suppresses inflammasome activity, and that desumoylation of NLRP3 by the SENP6 and SENP7 proteases promotes NLRP3 activation.
- Rachael Barry
- , Sidonie Wicky John
- & Pascal Meier
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Article
| Open AccessCaspases maintain tissue integrity by an apoptosis-independent inhibition of cell migration and invasion
In addition to regulating programmed cell death, caspases also have non-apoptotic roles. Here, the authors show that low level caspase activity prevents cell migration to maintain tissue integrity.
- Anna Gorelick-Ashkenazi
- , Ron Weiss
- & Eli Arama
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Article
| Open AccessConformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis
RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.
- Emma J. Petrie
- , Jarrod J. Sandow
- & James M. Murphy
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Article
| Open AccessSingle-walled carbon-nanohorns improve biocompatibility over nanotubes by triggering less protein-initiated pyroptosis and apoptosis in macrophages
Carbon-nanohorns have a unique morphology and structure yet little is known about the biocompatibility. Here, the authors investigate the biocompatibility and bio-interaction of carbon nanohorns, compare them to carbon nanotubes and show the superior biocompatibility and safety of the nanohorns.
- Bing He
- , Yujie Shi
- & Qiang Zhang
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Article
| Open AccessNon-invasive detection of human cardiomyocyte death using methylation patterns of circulating DNA
The detection of cardiomyocyte death is a critical aspect in the diagnosis and monitoring of heart diseases. Here the authors show that cardiomyocyte-specific methylation patterns of circulating cell-free DNA may serve as a biomarker of cardiac cell death in infarcted and septic patients.
- Hai Zemmour
- , David Planer
- & Yuval Dor
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Article
| Open AccessShort-term activation of the Jun N-terminal kinase pathway in apoptosis-deficient cells of Drosophila induces tumorigenesis
Jun N-terminal kinase (JNK) is necessary for development in tumours, indicating it may play tumour-promoting roles; however, the experimental analysis of the role of JNK in proliferation is hindered by its pro-apoptotic activity. Here the authors carry out experiments in Drosophila with genetic backgrounds that make cells refractory to apoptosis to definitely prove the JNK pathway contribution to tumorigenesis.
- Noelia Pinal
- , María Martín
- & Ginés Morata