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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function
The lipid kinase PI3KC2α is essential for embryogenesis, yet its role in adult homeostasis is unknown. Here, the authors show that PI3KC2α regulates the structure of the internal membrane reserves of murine megakaryocytes and platelets, affecting the platelets’ adhesiveness and prothrombotic function.
- Jessica K. Mountford
- , Claire Petitjean
- & Shaun P. Jackson
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A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
Receptor Interacting Protein Kinase 2 (RIPK2) mediates innate immune signalling in response to intracellular pathogens, but its aberrant activation contributes to autoimmune pathologies. Here Nachbur et al.describe a RIPK2 inhibitor that is effective in a mouse model of multiple sclerosis.
- Ueli Nachbur
- , Che A. Stafford
- & John Silke
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IRF8 directs stress-induced autophagy in macrophages and promotes clearance of Listeria monocytogenes
Autophagy is critical for pathogen clearance by innate immune cells. Here the authors show that IRF8 is activated in response to autophagy-inducing stimuli, promotes autophagic progression by driving transcription of autophagy genes and is critical for clearance of intracellular bacteria.
- Monica Gupta
- , Dong-Mi Shin
- & Keiko Ozato
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ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells
How the magnitude of the response is regulated in different T-cell memory subsets remains poorly understood. Here the authors show that miR-181 lowers the threshold of Th17 memory activation via sustained Erk phosphorylation, while Erk-dependent induction of ID3 limits Th17 activity at later time.
- Federico Mele
- , Camilla Basso
- & Silvia Monticelli
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Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development
Wnt receptors and the cytoplasmic signalling adaptor, dishevelled (Dvl), are upregulated in cancer and result in elevated canonical Wnt signalling. Here the authors show that the adaptor protein Epsin acts as a chaperone that protects Dvl from degradation thereby contributing to excess Wnt signalling and colon cancer growth.
- Baojun Chang
- , Kandice L. Tessneer
- & Hong Chen
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HEB associates with PRC2 and SMAD2/3 to regulate developmental fates
In embryonic stem cells, extracellular signals are required to derepress developmental promoters to drive lineage specification, but the proteins involved in this process remain unknown. Here the authors show that the protein HEB directly associates with the Polycomb repressive complex 2 at genes involved in mesoderm and endoderm specification.
- Se-Jin Yoon
- , Joseph W. Foley
- & Julie C. Baker
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| Open AccessOriented cell division shapes carnivorous pitcher leaves of Sarracenia purpurea
The pitcher-shaped leaf of the carnivorous plant Sarracenia purpurea acts as a pitfall trap to capture small animals. Here, Fukushima et al. analyse pitcher leaf development and propose that this unusual shape evolved from ancestral planar leaves through changes in the orientation of cell division.
- Kenji Fukushima
- , Hironori Fujita
- & Mitsuyasu Hasebe
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Notch1–Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration
Many forms of collective cell migration are directed by specialized leader cells that have a distinct protrusive phenotype. Riahi et al.show that lateral inhibition mediated by Notch1–Dll4 signalling determines the stochastic emergence of leader cells in epithelial monolayers.
- Reza Riahi
- , Jian Sun
- & Pak Kin Wong
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TOPBP1 recruits TOP2A to ultra-fine anaphase bridges to aid in their resolution
During chromosome segregation sister chromatids can be entangled, resulting in anaphase bridges that must be resolved. Here, the authors report that topoisomerase IIβ binding protein 1 recruits topoisomerase IIα to centromere-associated ultra-fine anaphase bridges to enable their efficient resolution.
- Ronan Broderick
- , Jadwiga Nieminuszczy
- & Wojciech Niedzwiedz
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| Open AccessMitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity
Heat shock induces proteotoxic stress, and the cellular response is mediated by heat-shock factor 1 (HSF1). Here, Tan et al.show that following heat shock, mitochondrial SSBP1 translocates to the nucleus and binds HSF1 to enhance the expression of chaperones and support the maintenance of mitochondrial function.
- Ke Tan
- , Mitsuaki Fujimoto
- & Akira Nakai
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Organelles maintain spindle position in plant meiosis
In many plants, male meiosis involves two rounds of chromosome separation without cell division, resulting in two spindles in a single cell. Here Brownfield et al. show that an organelle band acts as a physical barrier between the spindles to ensure accurate chromosome segregation.
- Lynette Brownfield
- , Jun Yi
- & Claudia Köhler
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Article
| Open AccessPlastid establishment did not require a chlamydial partner
Primary plastids descend from an endosymbiosis involving cyanobacteria, an ancient eukaryotic host and, possibly, a chlamydial pathogen. Here, Domman and colleagues use sophisticated phylogenetic methods to show that Chlamydiaedid not play a role in establishing the primary plastid endosymbiosis.
- Daryl Domman
- , Matthias Horn
- & Tom A. Williams
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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis
Tumour-targeted antibodies can kill cancer cells by blocking pro-survival signalling or by delivering a toxin. Here the authors show that glypican-3 antibody fused to a bacterial toxin suppresses tumour growth more efficiently if designed to block Wnt signalling downstream of glypican-3.
- Wei Gao
- , Zhewei Tang
- & Mitchell Ho
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| Open AccessArtificial human Met agonists based on macrocycle scaffolds
Activation of the Met receptor by hepatocyte growth factor requires Met receptor dimerization. Here, the authors identify Met-binding peptide macrocycles that, in a dimeric form as a result of chemical crosslinking, induce Met receptor dimerization and activation in cultured human cells.
- Kenichiro Ito
- , Katsuya Sakai
- & Hiroaki Suga
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Integrin β1 controls VE-cadherin localization and blood vessel stability
The role of integrin β1 in angiogenesis is poorly understood. Here, the authors show that integrin β1 regulates murine angiogenesis and adherens junction integrity by controlling VE-cadherin localization, myosin light chain phosphorylation and the function of the Rap1/MRCK and Rho/Rho-kinase pathways.
- Hiroyuki Yamamoto
- , Manuel Ehling
- & Ralf H. Adams
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| Open AccessCenpj/CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of Ascl1
The proneural factor Ascl1/Mash1 is an important regulator of embryonic neurogenesis. Here the authors identify that the microcephaly protein Cenpj/CPAP is essential for several microtubule-dependent steps in the neurogenic program driven by Ascl1 in the developing cerebral cortex.
- Patricia P. Garcez
- , Javier Diaz-Alonso
- & François Guillemot
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| Open AccessDefective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy
Diabetic kidney disease is associated with ER stress in podocytes. Here the authors use various genetically modified mouse models to study ER-stress-related signalling pathways and propose a mechanistic framework that links insulin signalling with ER stress in podocytes of diabetic mice.
- Thati Madhusudhan
- , Hongjie Wang
- & Berend Isermann
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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation
Anticancer treatments are tested in mice housed below thermoneutrality which represents chronic cold-stress. Here Eng et al. show that these mice have activated stress responses leading to therapeutic resistance and that inhibiting adrenergic signaling increases efficacy of anticancer therapies.
- Jason W.-L. Eng
- , Chelsey B. Reed
- & Bonnie L. Hylander
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| Open AccessIdentification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
FOXM1, a transcription factor with roles in cell cycle progression, is highly expressed in the majority of solid tumours. Here the authors show that FOXM1 is an ideal therapeutic target in B-cell acute lymphoblastic leukaemia (ALL) due to its dispensability for normal B-cell development.
- Maike Buchner
- , Eugene Park
- & Markus Müschen
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Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages
Macrophages have a role in the pathogenesis of pulmonary emphysema. Here the authors show that inhalation—but not oral delivery—of the anti-osteoporosis drug alendronate attenuates lung damage in a mouse model of emphysema by inducing apoptosis of alveolar macrophages.
- Manabu Ueno
- , Toshitaka Maeno
- & Masahiko Kurabayashi
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Use of the CRISPR/Cas9 system as an intracellular defense against HIV-1 infection in human cells
The CRISPR/Cas9 system can be used for genome editing. Here, Liao et al. show that the system can be adapted to inhibit HIV expression and replication, excise the integrated HIV genome and provide long-term protection against new infections in human cells, including pluripotent stem cells.
- Hsin-Kai Liao
- , Ying Gu
- & Juan Carlos Izpisua Belmonte
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| Open AccessUpward synaptic scaling is dependent on neurotransmission rather than spiking
Synaptic upscaling is characterized by an increase in the strength of excitatory inputs to a neuron as a compensatory response to chronic reductions in spiking activity. Here, the authors demonstrate that reduced glutamatergic transmission, rather than reduced spiking activity, directly triggers upscaling.
- Ming-fai Fong
- , Jonathan P. Newman
- & Peter Wenner
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MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
Accumulation of mitochondrial DNA (mtDNA) mutations is linked to severe anaemia by an unknown mechanism. Here the authors show that excessive mtDNA mutations impair mitochondrial expulsion during erythropoiesis leading to augmented erythrocyte clearance and anaemia in mice and humans.
- K.J. Ahlqvist
- , S. Leoncini
- & A. Suomalainen
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Chromokinesin Kid and kinetochore kinesin CENP-E differentially support chromosome congression without end-on attachment to microtubules
Alignment of chromosomes at the spindle equator involves two kinesin family molecular motors, Kid and CENP-E. Here, Iemura and Tanaka show differential contributions of these motors, whereby Kid promotes partial alignment before end-on microtubule attachment to chromosomes, and CENP-E promotes alignment when microtubules are stabilized.
- Kenji Iemura
- & Kozo Tanaka
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CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling
Mutations in the CCM3 gene in humans lead to severe forms of cerebral cavernous malformation. Here, Lant et al. shed light on the mechanism of CCM-3 function in C. elegans, and show that CCM-3 ablation leads to defects in excretory canal extension and the formation of cysts reminiscent of human malformations.
- Benjamin Lant
- , Bin Yu
- & W Brent Derry
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Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis
Ubiquinone is a redox-active molecule that is involved in mitochondrial electron transfer. Here, Wang et al. report a mouse model that allows for temporarily controlled ubiquinone synthesis, and show that shortened lifespan associated with lack of ubiquinone can be reversed if ubiquinone biosynthesis is restored.
- Ying Wang
- , Daniella Oxer
- & Siegfried Hekimi
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| Open AccessMicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres
Maturation of antibody-producing B cells in germinal centers is orchestrated by T follicular helper cells. Here Pratama et al. show that miR-146a negatively regulates T follicular helper cells by targeting ICOS-ICOS ligand signaling in germinal centers.
- Alvin Pratama
- , Monika Srivastava
- & Carola G. Vinuesa
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| Open AccessChromatin organization at the nuclear pore favours HIV replication
Retroviruses such as HIV integrate into the host genome as an essential step prior to their replication. Here Lelek et al. identify nuclear pore complex proteins that are essential for HIV nuclear import and productive integration, and show that the intranuclear protein Tpr influences integration into transcriptionally active chromatin.
- Mickaël Lelek
- , Nicoletta Casartelli
- & Francesca Di Nunzio
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| Open AccessHighly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour
Alterations of p53 are associated with more than half of all human cancers. Here the authors present a new pH-sensitive nanoparticle that is delivered via systemic circulation and combines gene delivery to restore p53 with expression of Killerred protein to induce photosensitization.
- S.-Ja Tseng
- , Zi-Xian Liao
- & Ivan M. Kempson
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PRMT9 is a Type II methyltransferase that methylates the splicing factor SAP145
Protein arginine methylation is an abundant post-translational modification often associated with RNA-binding proteins. Here the authors show that the previously uncharacterized PRMT9 enzyme catalyses the symmetrical methylation of SAP145, which promotes its association with the SMN complex and regulates splicing.
- Yanzhong Yang
- , Andrea Hadjikyriacou
- & Mark T. Bedford
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| Open AccessDisruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
STAT3 is an intracellular transducer of cytokine signals that cooperates with Ras in tumour formation and is often activated in lung cancer. Here the authors show that STAT3 acts as a tumour suppressor in a mouse model of Kras-driven lung adenocarcinoma.
- Beatrice Grabner
- , Daniel Schramek
- & Emilio Casanova
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| Open AccessCheckpoints are blind to replication restart and recombination intermediates that result in gross chromosomal rearrangements
Homologous recombination can overcome replication fork inactivation, but this can cause gross chromosomal rearrangements. Here, the authors show that DNA damage and intra-S phase checkpoints are blind to chromosome rearrangement in the first cell cycle, and are only induced in the second cell cycle.
- Saed Mohebi
- , Ken’Ichi Mizuno
- & Johanne M. Murray
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Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis
The spatial orientation of cell divisions is fundamental for tissue architecture and homeostasis but the extracellular cues regulating this process are largely unknown. Here, the authors show that Semaphorin3B released from the floor plate and the nascent choroid plexus controls progenitor division orientation in the developing mouse spinal cord.
- Elise Arbeille
- , Florie Reynaud
- & Valérie Castellani
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| Open AccessArabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth
Suppression of MutS HOMOLOGUE 1 (MSH1), a plant protein targeted to mitochondria and plastids, causes a variety of phenotypes. Here Virdi et al. show that MSH1 depletion in Arabidopsisresults in heritable changes in nuclear DNA methylation, which can lead to enhanced growth vigour.
- Kamaldeep S. Virdi
- , John D. Laurie
- & Sally A. Mackenzie
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| Open AccessComplement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling
The role of macrophages in hypertension-induced arterial remodeling is poorly understood. Here, Sumida et al. show that high blood pressure drives the alternatively activated macrophages to secrete complement C1q protein, which in turn elicits proliferative β-catenin signalling in the arterial smooth muscle cells.
- Tomokazu Sumida
- , Atsuhiko T. Naito
- & Issei Komuro
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Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking
Secretory vesicles must cross a dense cortical actin network to dock and fuse with the plasma membrane. Papadopulos et al. reveal that, in neurosecretory cells, relaxation of this network acts as a 'casting net', driving tethered vesicles towards the plasma membrane.
- Andreas Papadopulos
- , Guillermo A. Gomez
- & Frederic A. Meunier
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Engineered pairs of distinct photoswitches for optogenetic control of cellular proteins
Photoreceptor-based photoswitches have proved to be powerful tools for the specific control of protein activity in live cells. Here the authors describe Magnets, a new set of photoswitches based on the Vivid photoreceptor with enhanced hetero-dimerization specificity and variable activation kinetics.
- Fuun Kawano
- , Hideyuki Suzuki
- & Moritoshi Sato
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| Open AccessReal-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation
CD8+ memory T cells appear during infection via a process of selection and differentiation that remains poorly understood. Using a fluorescent indicator of cell cycle progression, Kinjyo et al. show that slow-cycling memory precursors are derived from fast-cycling-activated T cells in influenza-infected mice.
- Ichiko Kinjyo
- , Jim Qin
- & Wolfgang Weninger
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| Open AccessCyclic stretching of soft substrates induces spreading and growth
Cells grown on a stiff substrate are stimulated through physical cues to spread, create actin stress fibres and proliferate. Here Cui et al. show that cyclic stretching cells on a soft pillar substrate has the same effect as growth on a stiff substrate, and results in nuclear translocation of YAP and MRTF-A.
- Yidan Cui
- , Feroz M. Hameed
- & Michael Sheetz
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A mechanically sensitive cell layer regulates the physical properties of the Arabidopsis seed coat
Mechanical signalling is an important regulator of plant development. Here, Creff et al.propose that the perception of mechanical signals in growing seeds by a specific cell layer in the seed coat controls the accumulation of gibberellic acid and links mechanical signals to the regulation of seed size.
- Audrey Creff
- , Lysiane Brocard
- & Gwyneth Ingram
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Metabolic cross-feeding via intercellular nanotubes among bacteria
Some bacteria can form nanotubes to transfer proteins and plasmids between neighbouring cells. Here, the authors show that nanotubes can also mediate the exchange of cytoplasmic amino acids between cells of the same or different bacterial species.
- Samay Pande
- , Shraddha Shitut
- & Christian Kost
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Nutritional stress induces exchange of cell material and energetic coupling between bacterial species
Bacterial communities adapt to changing environments by modulating patterns of nutrient flow between species. Benomar et al. show that under nutrient stress, the sulfate-reducing bacterium Desulfovibrio vulgaris can exchange cytoplasmic material with Clostridium acetobutylicum, altering metabolic flux.
- Saida Benomar
- , David Ranava
- & Marie-Thérèse Giudici-Orticoni
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Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia
Acinar-to-ductal metaplasia (ADM) is a potential early step in the development of pancreatic cancer. Here, using an in vitromodel of ADM, the authors show that protein kinase D1 (PKD1) is required for TGFα- or KRAS-induced ADM through Notch activation.
- Geou-Yarh Liou
- , Heike Döppler
- & Peter Storz
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Substrate stress relaxation regulates cell spreading
Studies of cellular mechanotransduction commonly use elastic substrates, whereas biological substrates are viscoelastic, exhibiting stress relaxation. Here, the authors show through computational modelling and experiments that viscoelastic substrates can stimulate cell spreading to a greater extent than purely elastic substrates with the same initial stiffness.
- Ovijit Chaudhuri
- , Luo Gu
- & David J. Mooney
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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In vivo odourant response properties of migrating adult-born neurons in the mouse olfactory bulb
Juxtaglomerular neurons (JGNs) of the mammalian olfactory bulb are generated throughout life, but when and how these adult-born cells acquire responsiveness to sensory stimuli remains unknown. Here, the authors use in vivotwo-photon imaging to monitor the migration and integration of adult-born JGNs and their sensory response properties.
- Yury Kovalchuk
- , Ryota Homma
- & Olga Garaschuk
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Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue
The ciliary margin of the eye functions as a source of multipotent progenitor cells in certain organisms but whether it plays this role in humans has not been easy to study. Here the authors culture human embryonic stem cells that self-organize into retinal tissue, and show that ciliary margin-like growth zones emerge from the developing human retinal tissue and contain stem cell niches.
- Atsushi Kuwahara
- , Chikafumi Ozone
- & Yoshiki Sasai
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Article
| Open AccessA balance between membrane elasticity and polymerization energy sets the shape of spherical clathrin coats
A relationship between membrane tension and clathrin polymerization during endocytosis has not been experimentally established. Here, the authors show using an in vitroreconstituted system and theoretical modelling that membrane tension regulates clathrin polymerization into spherical cages by varying the membrane budding energy.
- Mohammed Saleem
- , Sandrine Morlot
- & Aurélien Roux
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Article
| Open AccessRIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.
- Kate E. Lawlor
- , Nufail Khan
- & James E. Vince
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