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| Open AccessApoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis
Mucins on the surface of healthy T cells limit their phagocytic uptake by macrophages. Here the authors show that upon apoptosis induction in T cells, surface mucins are cleaved and released by ADAM10 to promote efferocytosis of the apoptotic cells.
- Linnea Z. Drexhage
- , Shengpan Zhang
- & Quentin J. Sattentau
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Article
| Open AccessChemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis
Deregulation of BCL-2 proteins ensures resistance to apoptosis. Here, the authors describe cytosolic BAX dimers, which in cancer cells inhibit BAX activation and they develop a strategy to modulate BAX dimers to potentiate BAX-mediated apoptosis.
- Nadege Gitego
- , Bogos Agianian
- & Evripidis Gavathiotis
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Article
| Open AccessMegakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Circulating cell-free DNA (cfDNA) has diagnostic potential, and clarifying its origins will aid in the minimally-invasive detection and monitoring of disease. Here, authors find that physiologically, megakaryocytes are major sources of cfDNA, while erythroblasts also release small amounts of cfDNA.
- Joshua Moss
- , Roni Ben-Ami
- & Yuval Dor
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Article
| Open AccessFibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
Fibroblast growth factor (FGF)18 plays pleiotropic roles, including bone development and carcinogenesis, however, its precise role in liver fibrosis remains incompletely understood. Here, the authors show that FGF18 promotes liver fibrosis by stimulating hepatic stellate cell proliferation, without concomitant upregulation of profibrotic genes.
- Yuichi Tsuchiya
- , Takao Seki
- & Hiroyasu Nakano
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Article
| Open AccessFGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice
Hepatic ischemia-reperfusion injury (IRI) is a common complication that occurs during hepatic resection and transplantation. Here the authors show that Hepatic stellate cells secrete FGF18 which alleviates hepatocyte injury by USP16/KEAP1/Nrf2 signaling.
- Gaozan Tong
- , Yiming Chen
- & XiaoKun Li
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Article
| Open AccessExtracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4
Dying cells display an “eat me” signal through phospholipid scrambling. Here, the authors show that activation of the plasma membrane-bound Xkr4 scramblase requires extracellular calcium as a “molecular glue” for connecting transmembrane regions.
- Panpan Zhang
- , Masahiro Maruoka
- & Jun Suzuki
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Article
| Open AccessNacα protects the larval fat body from cell death by maintaining cellular proteostasis in Drosophila
Protein homeostasis is crucial for maintaining cellular homeostasis. Here, the authors show that proteotoxic stress caused by Nacalpha mutants specifically and progressively induces cell death in the apoptosis-resistant Drosophila larval fat body.
- Takayuki Yamada
- , Yuto Yoshinari
- & Takashi Nishimura
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Article
| Open AccessSNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development
The balance of stem cell maintenance, differentiation, and programmed death is critical for proper development. Here they show that SNIP1 is critical for stem cell survival and differentiation in the developing brain where it acts downstream of TGFb and NFkB and regulates PRC2 activities for governing cell fates.
- Yurika Matsui
- , Mohamed Nadhir Djekidel
- & Jamy C. Peng
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Article
| Open AccessStructures of p53/BCL-2 complex suggest a mechanism for p53 to antagonize BCL-2 activity
The human tumor suppressor p53 interacts with the BCL-2 family proteins to regulate apoptosis. Here, the authors solve the structures of p53 in complex with the antiapoptotic protein BCL-2 and suggest a mechanism by which p53 promotes apoptosis by competitively antagonizing the interaction of BCL-2 with pro-apoptotic BCL-2 family proteins.
- Hudie Wei
- , Haolan Wang
- & Yongheng Chen
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Article
| Open AccessCytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle
The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.
- Paul T. Morse
- , Gonzalo Pérez-Mejías
- & Maik Hüttemann
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Article
| Open AccessTisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice
Cardiac I/R injury is a deleterious issue in the clinic. Here, the authors show that Tisp40 facilitates HBP flux and protein O-GlcNAcylation through binding to the promoter of GFPT1, thereby preventing cardiac I/R injury.
- Xin Zhang
- , Can Hu
- & Qi-Zhu Tang
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Article
| Open AccessDynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.
- Danielle S. Potter
- , Ruochen Du
- & Anthony Letai
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Article
| Open AccessRegorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis
The mechanism underlying regorafenib’s hepatotoxicity during anticancer therapy remains elusive. Here, the authors show regorafenib inhibits the phosphorylation of EphA2 at Ser897 resulting in the accumulation of p53 and contributes to hepatocytes apoptosis and the formation of hepatotoxicity.
- Hao Yan
- , Wentong Wu
- & Peihua Luo
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Article
| Open AccessUDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
The mechanism underlying hepatocytes apoptosis, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here, the authors identify UGDH and its catalytic product UDP-glucuronate as suppressors of NASH-associated liver damage by inhibiting RIPK1- dependent hepatocyte apoptosis.
- Tao Zhang
- , Na Zhang
- & Jinyang Gu
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Article
| Open AccessPRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer
Despite being an effective treatment for hepatocellular carcinoma (HCC), resistance to oxaliplatin presents a major obstacle. Here, the authors identify PRMT3-induced methylation of IGF2BP1 resulting in HEG1 stabilisation as a mechanism of oxaliplatin resistance in HCC.
- Yunxing Shi
- , Yi Niu
- & Binkui Li
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Article
| Open AccessExecutioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis
During apoptosis, mitochondrial outer membrane permeabilization results in cytosolic mitochondrial RNA (mtRNA). Here, the authors demonstrate that caspase-3/7 inhibition promotes a cytosolic mtRNA-driven Type I interferon response via MDA5/MAVS/IRF3, increasing the immunogenicity of chemotherapy-induced apoptosis.
- Shane T. Killarney
- , Rachel Washart
- & Kris C. Wood
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Article
| Open AccessTHADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass
THADA has been identified as a type 2 diabetes-associated gene whose function is not fully understood. Here the authors report that THADA deficiency protects mice from hyperglycemia and glucose intolerance by promoting insulin secretion and inhibiting β-cell apoptosis, suggesting THADA could be explored as a potential therapeutic target for diabetes.
- Yuqing Zhang
- , Shan Han
- & Han Zhao
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Article
| Open AccessUnique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.
- Hirofumi Nagao
- , Ashok Kumar Jayavelu
- & C. Ronald Kahn
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| Open AccessA genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis
Efferocytosis describes the engulfment and clearance of apoptotic cells by phagocytes. Here the authors identify in primary mouse macrophage WDFY3 as a regulator for efferocytosis, in which c-terminal WDFY3 is sufficient to modulate degradation while full-length WDFY3 is required to modulate the uptake of apoptotic cells.
- Jianting Shi
- , Xun Wu
- & Hanrui Zhang
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Article
| Open AccessTargeting anti-apoptotic pathways eliminates senescent melanocytes and leads to nevi regression
Cutaneous hyperpigmented lesions, including nevi, are populated by senescent melanocytes. Here the authors provide evidence for a novel strategy based on combining inhibition of the BCL-2 and MCL1 anti-apoptotic pathways that selectively eliminates senescent melanocytes in culture and in vivo.
- Jaskaren Kohli
- , Chen Ge
- & Marco Demaria
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Article
| Open AccessSENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation
The receptor-interacting protein (RIPK1) promotes cell death and contributes to nonalcoholic steatohepatitis pathogenesis. Here the authors report that a SUMO-specific protease, SENP1, deSUMOylates RIPK1 and inhibits cell death in a mouse model of non-alcoholic fatty liver disease.
- Lingjie Yan
- , Tao Zhang
- & Daichao Xu
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Article
| Open AccessL-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans
How dietary restriction increases longevity is still not fully understood. Here, the authors demonstrate that L-threonine is an essential mediator of dietary restriction that prevents age-induced ferroptosis and that dietary supplementation promotes healthy ageing.
- Juewon Kim
- , Yunju Jo
- & Dongryeol Ryu
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Article
| Open AccessBNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.
- Feixia Wang
- , Yifeng Liu
- & Dan Zhang
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Article
| Open AccessExploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.
- Cameron S. Fraser
- , Johan K. E. Spetz
- & Kristopher A. Sarosiek
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Article
| Open AccessMYC sensitises cells to apoptosis by driving energetic demand
MYC activation can sensitise cells to apoptosis upon glutamine withdrawal. Here the authors show that MYC activation enhances global transcription and translation that creates a metabolic demand, while glutamine limitation causes a metabolic demand and supply imbalance through loss of TCA energetics and thus, sensitises cells to apoptosis.
- Joy Edwards-Hicks
- , Huizhong Su
- & Andrew J. Finch
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Article
| Open AccessMicrotubule disassembly by caspases is an important rate-limiting step of cell extrusion
Using the Drosophila pupal notum, the authors demonstrate that the disassembly of microtubules by effector caspases initiate cell extrusion independently of actomyosin regulation, thus providing insights into how caspases orchestrate dying epithelial cell expulsion.
- Alexis Villars
- , Alexis Matamoro-Vidal
- & Romain Levayer
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Article
| Open AccessCo-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
Deregulation of the BCL-2 family interactions ensures cancer resistance to apoptosis and is a major challenge to current treatments. Here the authors describe a novel therapeutic strategy to overcome two anti-apoptotic mechanisms for cancer therapy.
- Andrea Lopez
- , Denis E. Reyna
- & Evripidis Gavathiotis
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Article
| Open AccessEndogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity
Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products.
- Carla Umansky
- , Agustín E. Morellato
- & Lucas B. Pontel
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Article
| Open AccessSomatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy
Here the authors show that elimination of germ cells carrying damaged genomes is regulated by intestinal stress signalling in nematodes. Failure of the intestinal signalling results in stress-induced aneuploidy indicating that environmental stress impacts inheritance.
- Najmeh Soltanmohammadi
- , Siyao Wang
- & Björn Schumacher
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Article
| Open AccessThe IGFBP3/TMEM219 pathway regulates beta cell homeostasis
In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
- Francesca D’Addio
- , Anna Maestroni
- & Paolo Fiorina
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Article
| Open AccessStructural basis of BAK activation in mitochondrial apoptosis initiation
The authors show that the mechanism of BAK activation in mitochondrial apoptosis involves cooperation between direct activation by BH3-only protein BID and BAK autoactivation, providing a unifying basis for BAK triggering by BH3 ligands.
- Geetika Singh
- , Cristina D. Guibao
- & Tudor Moldoveanu
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Article
| Open AccessRIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis
RIPK1 regulates inflammation and cell death and is inhibited by phosphorylation on numerous residues. Here, the authors use a CRISPR whole genome screen to identify that protein phosphatase 1 regulatory subunit 3G regulates RIPK1 apoptotic and necroptotic activity as well as inflammation.
- Jingchun Du
- , Yougui Xiang
- & Zhigao Wang
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Article
| Open AccessStarvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis
Upon starvation, cells coordinate protein disposal to recycle amino acids, although the role of the proteasome has been unclear. Here, the authors show that in the mammalian nucleus, proteasomes form condensates that dissolve following nutrient replenishment.
- Maxime Uriarte
- , Nadine Sen Nkwe
- & El Bachir Affar
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Article
| Open AccessApoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death
Apoptosis is a cellular process that eliminates damaged or superfluous cells. Here the authors show that cells undergoing apoptotic stresss secrete the growth factor FGF2, which upregulates pro-survival BCL-2 proteins in neighbouring cells, thereby promoting their survival.
- Florian J. Bock
- , Egor Sedov
- & Stephen W. G. Tait
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Article
| Open AccessSMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria
SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca2+ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.
- Yibo Xue
- , Jordan L. Morris
- & Sidong Huang
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Article
| Open AccessTargeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer
The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.
- Jianhuang Lin
- , Heng Liu
- & Rugang Zhang
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Article
| Open AccessCytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity
Cytotoxic CD8+ T lymphocytes (CTL) often fail to kill tumour cells in one-to-one interactions. Here the authors show that these sublethal interactions from multiple CTL can add up over time and achieve tumour cell killing by additive cytotoxicity.
- Bettina Weigelin
- , Annemieke Th. den Boer
- & Peter Friedl
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Article
| Open AccessThe Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis
Diabetes is characterized by dysfunction and loss of beta-cells, and promoting beta-cell survival is of therapeutic interest. Here the authors show that Large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, induces beta-cell failure through mTORC1 hyperactivation and autophagic flux suppression.
- Ting Yuan
- , Karthika Annamalai
- & Amin Ardestani
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Article
| 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 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 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 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 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 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 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 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