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| Open AccessA ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis
UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.
- Davide Pradella
- , Gianluca Deflorian
- & Claudia Ghigna
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Article
| Open AccessTwo parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis
The metabolism of amino acids and the cellular energy sensor AMPK are both connected to mTORC1, but the pathway details have not been well defined. Here, the authors show that glutamine metabolism and mTORC1 have two regulatory connections with relevance to cancer therapeutics design.
- Clément Bodineau
- , Mercedes Tomé
- & Raúl V. Durán
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Article
| Open AccessNEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.
- Huibing Wang
- , Weiwei Qi
- & Junying Yuan
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| Open AccessMultifaceted mechanisms mediating cystine starvation-induced ferroptosis
The cyst(e)ine/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis is the most frequently targeted pathway to trigger the ferroptosis cascade and suppress tumor growth. Two recent studies present additional mechanisms underlying cystine starvation-induced ferroptosis apart from impaired GSH synthesis.
- Zhennan Shi
- , Nathchar Naowarojna
- & Yilong Zou
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Article
| Open AccessChloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis
The serine/threonine kinase WNK1 is an inhibitor of chloride efflux. Here the authors show that this inhibition is a means of negatively regulating the activation of the NLRP3 inflammasome in macrophages, leading to reduced inflammatory responses.
- Lindsey Mayes-Hopfinger
- , Aura Enache
- & Emad S. Alnemri
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| Open AccessDysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury
Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis—a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.
- Wulf Tonnus
- , Claudia Meyer
- & Andreas Linkermann
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Article
| Open AccessStructure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
The small molecule DNMDP acts as a velcrin by inducing complex formation between phosphodiesterase PDE3A and SLFN12, which kills cancer cells that express sufficient levels of both proteins. Here, the authors present the cryo-EM structure of the DNMDP-stabilized PDE3A-SLFN12 complex and show that SLFN12 is an RNase. PDE3A binding increases SLFN12 RNase activity, and SLFN12 RNase activity is required for DNMDP-mediated cancer cell killing.
- Colin W. Garvie
- , Xiaoyun Wu
- & Heidi Greulich
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Article
| Open AccessSETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome
Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
- Federica Banfi
- , Alicia Rubio
- & Alessandro Sessa
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Article
| Open AccessIron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy
Iron is essential during pregnancy for embryo and placental development and maternal health. However, in this study using mouse models, the authors demonstrate that excess maternal iron causes adverse embryo outcomes in pregnancies with underlying systemic inflammation.
- Allison L. Fisher
- , Veena Sangkhae
- & Elizabeta Nemeth
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Article
| Open AccessiPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4
p53 is able to induce ferroptosis in response to reactive oxygen species (ROS)-induced stress and suppresses tumour growth. Here, the authors show that iPLA2β suppresses p53-medated ferroptosis by cleaving and detoxifying peroxidized lipids and that this is independent of canonical ferroptosis regulator GPX4.
- Delin Chen
- , Bo Chu
- & Wei Gu
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Article
| Open AccessUbiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance
Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.
- Laura Ramos Garcia
- , Tencho Tenev
- & Pascal Meier
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Article
| Open AccessTNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread
Controlled cell death can be an efficient anti-viral strategy, but also leads to tissue damage and needs to be balanced. Oyler-Yaniv et al. combine mathematical modelling and microscopy to show that exposure to TNF in response to viral infection causes cells to tune their speed-vs-accuracy trade-off in cell death decision to limit HSV-1 spread.
- Jennifer Oyler-Yaniv
- , Alon Oyler-Yaniv
- & Roy Wollman
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Article
| Open AccessZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
Tumour necroptosis is regulated by RIPK3 during tumour development. Here the authors show that ZBP1 is an upstream mediator of RIPK3 in tumour necroptosis and that glucose deprivation induces the release of mitochondrial DNA, which binds to ZBP1 to activate ZBP1-mediated necroptosis in breast cancer.
- Jin Young Baik
- , Zhaoshan Liu
- & Zheng-gang Liu
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Article
| Open AccessSelective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir
DEAD-box polypeptide 3 (DDX3) is a host protein belonging to the family of ATP-dependent RNA helicases. Here, the authors demonstrate that DDX3 inhibitors reverse HIV-1 latency and selectively induce cell death in HIV-1-infected cell lines, primary CD4+ T cells and in CD4+ T cells from cART-suppressed people living with HIV-1.
- Shringar Rao
- , Cynthia Lungu
- & Tokameh Mahmoudi
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Article
| Open AccessDNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells
Caspase independent alternative cell death (ACD) pathways exist, but have been largely investigated under non-physiological conditions. Here, the authors show that Drosophila primordial germ cells normally elicit DNase II-dependent DNA damage, triggering a parthanatos-like ACD pathway.
- Lama Tarayrah-Ibraheim
- , Elital Chass Maurice
- & Eli Arama
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Article
| Open AccessStructural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis
The structure of human tumor suppressor p53 in complex with the antiapoptotic protein BCL-xL reveals the basis of the p53–BCL-xL interaction and provides insight into the mechanisms of p53-mediated mitochondrial apoptosis.
- Hudie Wei
- , Lingzhi Qu
- & Yongheng Chen
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Article
| Open AccessConformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis
Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.
- Sarah E. Garnish
- , Yanxiang Meng
- & James M. Murphy
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Article
| Open AccessFerroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes
The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.
- Christina M. Bebber
- , Emily S. Thomas
- & Silvia von Karstedt
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Article
| Open AccessThe amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis
Receptor Interacting Protein Kinase 3 (RIPK3) has a key role in TNF-induced necroptosis. Here, the authors combine solid state NMR measurements, MD simulations and cell based assays to characterize mouse RIPK3 and they present the structure of the RIPK3 amyloid core.
- Xia-lian Wu
- , Hong Hu
- & Jun-xia Lu
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Article
| Open AccessmTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation
Glutathione peroxidase 4 (GPX4) inhibits ferroptosis, but protein synthesis is inefficient and costly. Here, the authors reveal that cystine uptake promotes GPX4 synthesis by activating mTORC1 and show that cancer cells are sensitized to ferroptosis by mTORC1 inhibition.
- Yilei Zhang
- , Robert V. Swanda
- & Boyi Gan
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Article
| Open AccessEltrombopag directly inhibits BAX and prevents cell death
The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.
- Adam Z. Spitz
- , Emmanouil Zacharioudakis
- & Evripidis Gavathiotis
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Article
| Open AccessCryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate
The core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP, coordinate cell fate. Here authors present the structure of full-length procaspase-8 in a complex with FADD and reveal how recruitment of c-FLIPS into this complex inhibits Caspase-8 activity.
- Joanna L. Fox
- , Michelle A. Hughes
- & Marion MacFarlane
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Article
| Open AccessNUPR1 is a critical repressor of ferroptosis
Ferroptosis is an iron-dependent form of oxidative cell death. In this study, the authors show that NUPR1, a stress-inducible transcription factor, may be a driver of ferroptosis resistance.
- Jiao Liu
- , Xinxin Song
- & Daolin Tang
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Article
| Open AccessThe long noncoding RNA lncCIRBIL disrupts the nuclear translocation of Bclaf1 alleviating cardiac ischemia–reperfusion injury
Cardiac ischemia–reperfusion (I/R) injury represents a key threat to human health. This study reveals that the long noncoding RNA lncRNA-CIRBIL is protective against I/R injury by inhibiting the nuclear translocation of Bclaf1.
- Yang Zhang
- , Xiaofang Zhang
- & Zhenwei Pan
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Article
| Open AccessAdhesion-mediated heterogeneous actin organization governs apoptotic cell extrusion
Cell extrusion regulates monolayer cell density and is critical in maintaining epithelia integrity, which has implications in homeostasis, development, and cancer progression. Here the authors describe how monolayer integrate mechanical signals from tissue mechanics, cell-cell adhesion, cell-substrate adhesion and cytoskeleton coordinate cell extrusion.
- Anh Phuong Le
- , Jean-François Rupprecht
- & Benoît Ladoux
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Article
| Open AccessUbiquitination of RIPK1 regulates its activation mediated by TNFR1 and TLRs signaling in distinct manners
RIPK1 is a critical kinase which mediates necroptosis, apoptosis and inflammation. Regulation of RIPK1 by ubiquitination is being intensively investigated. Here, the authors made knock-in RIPK1-K612R mice and demonstrate that this mutation alters the RIPK1 ubiquitinylation pattern and inhibits its prodeath kinase activity in response to TNFα but sensitizes cell death to TLRs signals.
- Xingyan Li
- , Mengmeng Zhang
- & Junying Yuan
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Article
| Open AccessThe CCR4–NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression
The CCR4-NOT complex catalyzes mRNA deadenylation and hence regulates protein translation. Here the authors show that CNOT3 regulation of this complex is needed for positive selection of thymocytes via a mechanism involving inhibition of pro-apoptotic gene expression.
- Taku Ito-Kureha
- , Takahisa Miyao
- & Tadashi Yamamoto
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Article
| Open AccessA macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus
Long non coding RNA molecules have been implicated in the immunopathology of a range of inflammatory pathologies. Here the authors show lncRNA MAARS regulates apoptosis via interaction with HuR in the context of atherosclerosis.
- Viorel Simion
- , Haoyang Zhou
- & Mark W. Feinberg
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Article
| Open AccessAkt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth
Although executioner caspase activation is considered terminal, some cells are capable of survival, suggesting additional regulation. Here, the authors show that cells in the Drosophila wing imaginal disc survive caspase activation via Akt1 and dCIZ1 and actively participate in tissue regeneration.
- Gongping Sun
- , Xun Austin Ding
- & Denise J. Montell
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Article
| Open AccessATF4 leads to glaucoma by promoting protein synthesis and ER client protein load
Glaucoma is the leading cause of irreversible blindness affecting over 70 million people worldwide. Here, the authors show that inhibition of chronic ER stress-induced ATF4-CHOP-GADD34 signaling pathway rescues pathology in mouse models of glaucoma, thus suggesting a possible treatment strategy.
- Ramesh B. Kasetti
- , Pinkal D. Patel
- & Gulab S. Zode
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Article
| Open AccessCrbn modulates calcium influx by regulating Orai1 during efferocytosis
Calcium flux must be carefully controlled during the phagocytosis of apoptotic cells (efferocytosis), although how this occurs is not fully understood. Here, the authors show that the Cereblon E3 ligase regulates Orai1 degradation and subsequently SOCE-mediated calcium influx.
- Hyunji Moon
- , Chanhyuk Min
- & Daeho Park
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Article
| Open AccessNeutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression
Tumour necrosis is associated with tumour aggressiveness and poor outcomes in patients with glioblastomas, but the underlying mechanisms remain poorly understood. Here, the authors show that in a xenograft mouse model of glioblastoma, tumour-infiltrating neutrophils amplify necrosis by promoting myeloperoxidase-induced tumour cell ferroptosis.
- Patricia P. Yee
- , Yiju Wei
- & Wei Li
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Article
| Open AccessIndirect regulation of HMGB1 release by gasdermin D
HMGB1 is an inflammatory mediator released by a variety of cell types. Here, the authors show that unlike IL-1β, HMGB1 is released non-specifically following cell lysis.
- Allen Volchuk
- , Anna Ye
- & Neil M. Goldenberg
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Article
| Open AccessLoss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology
Mandibuloacral dysplasias (MADs) are rare progeroid syndromes characterized by nuclear morphological and functional abnormalities. Here the authors report that loss of mitochondrial membrane protein MTX2 causes a progeroid MAD sharing clinical features with lamin-associated progeroid syndromes.
- Sahar Elouej
- , Karim Harhouri
- & Annachiara De Sandre-Giovannoli
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Article
| Open AccessGsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis
Impaired oligodendrocyte (OL) differentiation and remyelination after myelin damage in multiple sclerosis is associated with neurodegeneration. The authors show that Gsta4 is expressed during adult OL differentiation and identify it as a regulator of OL differentiation, survival, and remyelination.
- Karl E. Carlström
- , Keying Zhu
- & Fredrik Piehl
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Article
| Open AccessA fluorogenic cyclic peptide for imaging and quantification of drug-induced apoptosis
Programmed cell death or apoptosis is an essential biological process that is impaired in some diseases and can be used to assess the effectiveness of drugs. Here the authors design Apo-15 as a fluorogenic peptide for the detection and real-time imaging of apoptotic cells.
- Nicole D. Barth
- , Ramon Subiros-Funosas
- & Marc Vendrell
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Article
| Open AccessBasement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue
The molecular mechanisms regulating macrophage recruitment to tumors are unclear. Here, the authors use a Drosophila overgrowth model to show how damaged basement membranes recruit macrophages to undead tissue, via an interdependent effect of reactive oxygen species and matrix metalloproteinase 2.
- Neha Diwanji
- & Andreas Bergmann
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Article
| Open AccessVacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death
It is unclear whether 2D metal dichalcogenides (TMD) alone can cause ferroptotic cell death. Here, the authors show TMD nanosheets induced ferroptosis in mammalian cell lines and in a mouse model after aspiration of TMD materials into lungs, causing ferroptotic cell death.
- Shujuan Xu
- , Huizhen Zheng
- & Ruibin Li
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Article
| Open AccessCharacterization of an alternative BAK-binding site for BH3 peptides
Mitochondrial apoptosis is controlled by BCL2 family proteins, and the BH3-only proteins often act as sensors that transmit apoptotic signals. Here the authors show how the BH3-only proteins BMF and HRK can directly activate the BCL2 protein BAK and interact with BAK through an alternative binding groove.
- Kaiqin Ye
- , Wei X. Meng
- & Haiming Dai
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Article
| Open AccessAn alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12.
- Youwei Ai
- , Haibing He
- & Xiangbing Qi
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Article
| Open AccessEndothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion
Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.
- Maria I. Avrutsky
- , Crystal Colón Ortiz
- & Carol M. Troy
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Article
| Open AccessMLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis
Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis.
- Andre L. Samson
- , Ying Zhang
- & James M. Murphy
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Article
| Open AccessDistinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues
The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).
- Katherine A. Davies
- , Cheree Fitzgibbon
- & James M. Murphy
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Article
| Open AccessA missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Joanne M. Hildebrand
- , Maria Kauppi
- & John Silke
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Article
| Open AccessAn integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells
The cytokine IFNα is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells. Here, the authors provide a global multiomics view of IFNα-induced changes in human beta cells at the level of chromatin, mRNA and protein expression.
- Maikel L. Colli
- , Mireia Ramos-Rodríguez
- & Décio L. Eizirik
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Article
| Open AccessTNFAIP8 controls murine intestinal stem cell homeostasis and regeneration by regulating microbiome-induced Akt signaling
The molecular mechanisms that regulate intestinal Clu+ revival stem cells (revSCs) and their niche to enable regeneration in response to injury are unclear. Here, the authors show that mice without the phospholipid transport protein, TNFAIP8, causes less revSCs to be induced following injury.
- Jason R. Goldsmith
- , Nina Spitofsky
- & Youhai H. Chen
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Article
| Open AccessNaked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties
Naked mole rats are the longest-lived rodents and produce very-high-molecular-mass hyaluronan (vHMM-HA). Here the authors show that naked mole rat vHMM-HA is better at protecting mouse and human cells from cell cycle arrest and cell death, compared to the high-molecular-mass hyaluronan produced by these species.
- Masaki Takasugi
- , Denis Firsanov
- & Vera Gorbunova
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Article
| Open AccessPlasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection
Inflammasome activation is a response to bacterial infection but can cause damage and spread infection. Here, the authors use live single-cell imaging to show two mechanisms by which M. tuberculosis causes damage to human macrophage cell plasma membranes, resulting in activation of the NLRP3 inflammasome, pyroptosis and release of infectious particles.
- Kai S. Beckwith
- , Marianne S. Beckwith
- & Trude H. Flo
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Article
| 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