Featured
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Article
| Open AccessSWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia
Insulin secretion by β-cells is stimulated by glucose and is dependent on the induction of β-cell membrane depolarization, mainly driven by the closure of KATP channels, which in turn promotes voltage-gated Ca2+ channel opening. Here Kang et al. show that the volume-regulated anion channel, SWELL1, is involved in glucose-stimulated calcium increase and insulin secretion.
- Chen Kang
- , Litao Xie
- & Rajan Sah
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Article
| Open AccessMultiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts
During S phase of the cell cycle, transcription and replication need to be coordinated in order to avoid conflicts leading to potential genomic instability. Here, the authors find that Mrc1 integrates signals from different kinases to regulate replication during unscheduled transcription events.
- Alba Duch
- , Berta Canal
- & Francesc Posas
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Article
| Open AccessAMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation
AMPK activation inhibits cardiac hypertrophy. Here the authors show that this occurs independently of previously proposed mechanisms and that AMPK controls the phosphorylation of the aminotransferase GFAT, thereby preventing cardiac hypertrophy through the reduction of protein O-GlcNAcylation.
- Roselle Gélinas
- , Florence Mailleux
- & Luc Bertrand
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Article
| Open AccessActive and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes
S-palmitoylation regulation has been studied mostly in the cytosol and its role in mitochondria is unclear. Here the authors develop fluorescent mitochondria-targeted probes and find that depalmitoylation occurs in mitochondria and it’s influenced by alterations in mitochondrial lipid homeostasis.
- Rahul S. Kathayat
- , Yang Cao
- & Bryan C. Dickinson
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Article
| Open AccessLack of beta-arrestin signaling in the absence of active G proteins
Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.
- Manuel Grundmann
- , Nicole Merten
- & Evi Kostenis
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Article
| Open AccessEpsin and Sla2 form assemblies through phospholipid interfaces
Adapter proteins assist clathrin coated pit assembly. Here, the authors combine native mass spectrometry, crystallography and SAXS measurements and show that the membrane–proximal domains of the adaptor proteins epsin and Sla2 form complexes mediated through phosphatidylinositol 4,5-bisphosphate interfaces leading to assembly formation.
- Maria M. Garcia-Alai
- , Johannes Heidemann
- & Rob Meijers
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Article
| Open AccessQuantitative proteomics identifies redox switches for global translation modulation by mitochondrially produced reactive oxygen species
The role of reactive oxygen species (ROS) in signalling and specific targets is not fully understood. Here the authors perform a global proteomic analysis to delineate the yeast redoxome and show that increased levels of intracellular ROS caused by dysfunctional mitochondria decrease global protein synthesis.
- Ulrike Topf
- , Ida Suppanz
- & Bettina Warscheid
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Article
| Open AccessStress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival
Rbfox1, a pro-survival RNA-binding protein, is expressed in a complex manner and mediates diverse developmental processes. Here, the authors observe alternative splicing of Rbfox1 and stress-dependent regulation by miR-980 in Drosophila ovaries and Rbfox1 localisation in ribonucleoprotein granules in human cells.
- Mariya M. Kucherenko
- & Halyna R. Shcherbata
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Article
| Open AccessNeuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.
- André M. Miranda
- , Zofia M. Lasiecka
- & Gilbert Di Paolo
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Article
| Open AccessA biosensor-based framework to measure latent proteostasis capacity
A pool of quality control proteins (QC) maintains the protein-folding homeostasis in the cell, but its quantitative analysis is challenging. Here the authors develop a FRET sensor based on the protein barnase, able to quantify QC holdase activity and its ability to suppress protein aggregation.
- Rebecca J. Wood
- , Angelique R. Ormsby
- & Danny M. Hatters
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Article
| Open AccessOxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis
The cellular mechanisms underlying autophagy are conserved; however it is unclear how they evolved in higher organisms. Here the authors identify two oxidation-sensitive cysteine residues in the autophagy receptor SQSTM1/p62 in vertebrates which allow activation of pro-survival autophagy in stress conditions.
- Bernadette Carroll
- , Elsje G. Otten
- & Viktor I. Korolchuk
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Article
| Open AccessProtein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes
Protein phosphatase 5 (PP5) is expressed in many cell types but its role in cardiomyocytes is unknown. Here the authors show that PP5 binds and dephosphorylates elastic titin in cardiac sarcomeres, and that PP5 is increased in heart failure, reducing cardiomyocyte compliance.
- Judith Krysiak
- , Andreas Unger
- & Wolfgang A. Linke
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Article
| Open AccessInjury-activated glial cells promote wound healing of the adult skin in mice
The peripheral nervous system has been implicated in wound healing. Here, Parfejevs and colleagues report that cutaneous wounding in mice induces the de-differentiation and proliferation of Schwann cells, which disseminate into the wound bed, secrete soluble factors, and promote wound healing.
- Vadims Parfejevs
- , Julien Debbache
- & Lukas Sommer
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Article
| Open AccessSub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells
Topologically associating domain (TAD) boundaries in flies seem to be different from those in mammals. Here, the authors use Hi-C with sub-kb resolution to identify about 4000 TADs in flies, most demarcated by the insulator complexes BEAF-32/CP190 or BEAF-32/Chromator like CTCF/cohesin in mammals.
- Qi Wang
- , Qiu Sun
- & Zhifeng Shao
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Article
| Open AccessDeregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism
Alterations in the MAPK pathway are common in cancers, yet mutations are rarely found in patients. Here the authors find genomic amplifications of the PPP1CA gene in advanced and metastatic prostate cancer and identify a role for this phosphatase in the positive regulation of ERK signalling.
- Ming Chen
- , Lixin Wan
- & Pier Paolo Pandolfi
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Article
| Open AccessInteraction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability
SOCS3 is an important negative feedback inhibitor of JAK–STAT-mediated cytokine signalling. Here the authors implicate cavin-1 — an essential component of caveolae — in the recruitment of SOCS3 to the plasma membrane to prevent sustained cytokine receptor signalling.
- Jamie J. L. Williams
- , Nasser Alotaiq
- & Timothy M. Palmer
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Article
| Open AccessStructural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168
E3 ubiquitin ligase RNF168 is important for the repair of DNA double-strand breaks and recognizes ubiquitylated targets through two Ub-dependent DSB recruitment modules UDM1 and UDM2. Here the authors combine crystallography, cell biology and biochemical experiments to reveal how UDM1 and UDM2 interact with polyubiquitin chains.
- Tomio S. Takahashi
- , Yoshihiro Hirade
- & Shuya Fukai
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Article
| Open AccessImpaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney
Nephropathic cystinosis is a lysosomal storage disease characterized by proximal tubular cell dysfunction. Here Festa and colleagues show that these lysosomal alterations lead to defective autophagic clearance of mitochondria and increased oxidative stress that, in turn, activates the transcription factor ZONAB leading to impaired cell differentiation.
- Beatrice Paola Festa
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessSequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria
Mitochondrial Ca2+ homoeostasis is tightly regulated and export of Ca2+ is mediated by an Na+Ca2+ exchanger. Here authors show that in depolarised mitochondria the exchanger initially operates in reverse mode, transporting cytosolic Ca2+ into the matrix before it reverts to its forward mode state.
- Krishna Samanta
- , Gary R. Mirams
- & Anant B. Parekh
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Article
| Open AccessThe peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading
Pex1 and Pex6 form a heterohexameric Type-2 AAA-ATPase motor whose function in peroxisomal matrix-protein import is still debated. Here, the authors combine structural, biochemical, and cell-biological approaches to show that Pex1/Pex6 is a protein unfoldase, which supports a role in mechanical unfolding of peroxin proteins.
- Brooke M. Gardner
- , Dominic T. Castanzo
- & Andreas Martin
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Article
| Open AccessMembrane shape-mediated wave propagation of cortical protein dynamics
Traveling waves in the cell cortex can propagate much faster than actin waves, and the mechanism is unknown. Here the authors propose a mechanochemical feedback model for traveling waves that incorporates membrane shape changes and recruitment of F-BAR proteins that enables fast wave propagation.
- Zhanghan Wu
- , Maohan Su
- & Jian Liu
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Article
| Open AccessOxidation of Atg3 and Atg7 mediates inhibition of autophagy
A dysfunction of autophagy can be detected in aged tissues, but how this is regulated is unclear. Here, the authors show in vitro and in aged mice aorta, that inhibition of LC3 lipidation under conditions of oxidative stress causes oxidation of Atg3 and Atg7, preventing autophagosome maturation.
- Karen Frudd
- , Thomas Burgoyne
- & Joseph Robert Burgoyne
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Article
| Open AccessLoss of mtDNA activates astrocytes and leads to spongiotic encephalopathy
Astrocytes in the brain are metabolically dynamic. Here, Ignatenko, Chilov and colleagues delete mitochondrial DNA (mtDNA) in a cell type specific manner, and show that inactivation of mtDNA helicase Twinkle in astrocytes leads to spongiotic encephalopathy.
- Olesia Ignatenko
- , Dmitri Chilov
- & Anu Suomalainen
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Article
| Open AccessReplication-dependent size reduction precedes differentiation in Chlamydia trachomatis
The vegetative forms of chlamydiae (RBs) replicate within infected cells and then convert into infectious forms (EBs). Here, the authors use quantitative 3D electron microscopy and computer modeling to show that RB size decreases with replication, and conversion into EBs correlates with an RB size threshold.
- Jennifer K. Lee
- , Germán A. Enciso
- & Ming Tan
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Article
| Open AccessHomocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury
High homocysteine plasma levels are associated with cardiovascular diseases. Here, Li and colleagues find that homocysteine aggravates vascular injury by direct binding to the angiotensin II type 1 receptor (AT1R), identifying AT1R inhibition as a potential strategy to counteract the deleterious vascular effects of hyperhomocysteinemia.
- Tuoyi Li
- , Bing Yu
- & Wei Kong
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Article
| Open AccessLncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription
Little is known about the role of long lncRNAs in autophagy. The authors identify lncCAIF, and show that it suppresses cardiac autophagy and attenuates myocardial infarction by targeting p53 -mediated transcription of myocardin.
- Cui-Yun Liu
- , Yu-Hui Zhang
- & Kun Wang
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Article
| Open AccessERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma
In BRAF mutant melanoma, inhibition of ERK1/2 induces FOXD3 and mediates RAF inhibitor resistance. Here, the authors show that ERK1/2 mediated phosphorylation regulates sumoylation of SOX10 which activates FOXD3, and depletion of SOX10 sensitises BRAF mutant melanoma cells to RAF inhibitors.
- Shujun Han
- , Yibo Ren
- & Yongping Shao
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Article
| Open AccessThe opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling
Marginal zone B (MZB) cells shuttle between the marginal zone and lymphoid follicle to capture and present peripheral blood antigens. Here the authors show that shear force, such as blood flow from the sinus around the follicle, is a directional cue that induces MZB migration on ICAM-1, and that S1P signaling inhibits this directional migration.
- Kerry Tedford
- , Michael Steiner
- & Klaus-Dieter Fischer
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Article
| Open AccessSmall-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.
- Chensu Wang
- , Hanspeter Niederstrasser
- & Michael A. White
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Article
| Open AccessGlutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells
Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.
- Emmanuel Dornier
- , Nicolas Rabas
- & Jim C. Norman
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Article
| Open AccessA conserved ankyrin repeat-containing protein regulates conoid stability, motility and cell invasion in Toxoplasma gondii
Apicomplexan parasites such as Toxoplasma gondii possess a tubulin-rich structure called the conoid. Here, Long et al. identify a conoid protein that interacts with motor and structural proteins and is required for structural integrity of the conoid, parasite motility, and host cell invasion.
- Shaojun Long
- , Bryan Anthony
- & L. David Sibley
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Article
| Open AccessCircadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
Circadian clock regulates hepatic gene expression and functions. Here Chao et al. show that alteration of circadian clock genes by Period deletion induces polyploidy in hepatocytes due to impaired regulation of Erk signaling by mitogen-activated protein kinase phosphatase 1.
- Hsu-Wen Chao
- , Masao Doi
- & Hitoshi Okamura
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Article
| Open AccessWhole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation
Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that mark proteins for degradation, but there is a current lack of knowledge about their distinct functions and substrates. Here, the authors elucidate the cellular roles and substrates of these polymerases using comparative functional and proteomics analyses of tankyrase knockout cell lines.
- Amit Bhardwaj
- , Yanling Yang
- & Susan Smith
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Article
| Open AccessPolarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis
The formation of new blood vessels requires both polarized cell migration and coordinated control of endothelial cell contacts. Here, Cao and colleagues describe at the sub-cellular level the cytoskeletal and cell junction dynamics regulating these processes upon VEGF-induced cell elongation.
- Jiahui Cao
- , Manuel Ehling
- & Hans Schnittler
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Article
| Open AccessThe sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission
The dopamine transporter (DAT), a regulator of dopamine homeostasis in the brain, and sigma-1 receptor (σ1R), an endoplasmic reticulum membrane protein, are both implicated in drug addiction. In this work, the authors investigate how σ1R modulates DAT response to methamphetamine.
- Danielle O. Sambo
- , Min Lin
- & Habibeh Khoshbouei
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Article
| Open AccessThe HIV co-receptor CCR5 regulates osteoclast function
CCR5 is a co-receptor for HIV, and loss of function is associated with lower incidence of HIV but also with bone-destructive diseases. Here the authors show that ablation of CCR5 impairs osteoclast function and improves resistance to osteoporosis in mouse models.
- Ji-Won Lee
- , Akiyoshi Hoshino
- & Tadahiro Iimura
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Article
| Open AccessDual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways are essential for cancer cell survival. Here, the authors describes a molecule a131 with dual-inhibitory properties, which targets PI5P4K and mitosis, and it is involved in Ras/Raf/MEK/ERK and PI3K/Akt/mTOR crosstalk, thereby causing reversible growth arrest in normal cells and cell death of tumor cells.
- Mayumi Kitagawa
- , Pei-Ju Liao
- & Sang Hyun Lee
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Article
| Open AccessRevealing chiral cell motility by 3D Riesz transform-differential interference contrast microscopy and computational kinematic analysis
The lack of an appropriate method has hampered quantitative measurements of cell chirality. Here, the authors combine Riesz transform-differential interference contrast microscopy and computational kinematic analysis to reveal chiral cell motility of neuronal growth cone filopodia and cellular slime mold.
- Atsushi Tamada
- & Michihiro Igarashi
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Article
| Open AccessANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ
NF-κB activation mediated by TNFα has a critical role in inflammation; however, the underlying mechanisms await further investigation. Here the authors show that selective autophagy regulates NF-κB activation via an ANGPTL8/p62-IKKγ signaling axis.
- Yu Zhang
- , Xian Guo
- & Kun Huang
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Article
| Open AccessPAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle
Facioscapulohumeral muscular dystrophy is a myopathy linked to ectopic expression of the DUX4 transcription factor. The authors show that the suppression of targets genes of the myogenesis regulator PAX7 is a signature of FSHD, and might explain oxidative stress sensitivity and epigenetic changes.
- Christopher R. S. Banerji
- , Maryna Panamarova
- & Peter S. Zammit
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Article
| Open AccessShe1 affects dynein through direct interactions with the microtubule and the dynein microtubule-binding domain
Dynein is a microtubule motor the motility of which is affected by the microtubule-associated protein She1. Here, the authors show that She1 alters dynein stepping behavior and increases its microtubule affinity through simultaneous interactions with the microtubule and dynein microtubule binding domain.
- Kari H. Ecklund
- , Tatsuya Morisaki
- & Steven M. Markus
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Article
| Open AccessCell shape information is transduced through tension-independent mechanisms
It is not known whether the shape of a cell can regulate cellular phenotype independently. Here, the authors show that culturing kidney podocytes or smooth muscle cells on 3-D biomimetic surfaces results in phenotypic changes and that cell shape is sensed by integrin β3 in a tension-independent manner.
- Amit Ron
- , Evren U. Azeloglu
- & Ravi Iyengar
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Article
| Open AccessNuclear lamin A/C harnesses the perinuclear apical actin cables to protect nuclear morphology
An actin cap protects the morphology of the nucleus during cellular mechanical stress. Here, the authors show that the nuclear lamina protein lamin A/C mediates the formation of the actin cap in response to stress, and model the distribution of forces in the presence and absence of the actin cap.
- Jeong-Ki Kim
- , Arghavan Louhghalam
- & Dong-Hwee Kim
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Article
| Open AccessDNA damage causes rapid accumulation of phosphoinositides for ATR signaling
Phosphoinositides are enriched in the nucleus and accumulate upon DNA damage but their role in responding to DNA damage is poorly defined. Here, the authors show that phosphoinositides rapidly accumulate at DNA damage sites and are required for ATR recruitment and subsequent Chk1 activation.
- Yu-Hsiu Wang
- , Anushya Hariharan
- & Michael P. Sheetz
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Article
| Open AccessStochastic gene expression in Arabidopsis thaliana
Noisy gene expression can cause stochasticity in the expression of plant traits. Here, Araújo et al. use a dual reporter system of protein expression in Arabidopsis to show that expression noise is lowest in stomata relative to other tissues and that leaf cells are coupled with respect to noise.
- Ilka Schultheiß Araújo
- , Jessica Magdalena Pietsch
- & Martin Hülskamp
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Article
| Open AccessRNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin
The factors that link chromatin remodelling to nuclear envelope formation in the sperm pronucleus are not fully characterised. Here, the authors show that in RNA-depleted Xenopus laevis egg extracts, ELYS recruitment and nuclear pore complex formation are impaired, resulting in defective nuclear processes.
- Antoine Aze
- , Michalis Fragkos
- & Marcel Méchali
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Article
| Open AccessPI3Kδ activates E2F1 synthesis in response to mRNA translation stress
The oncogenic activity of EBNA1 protein is unknown; it contains a glycine and alanine repeat sequence (GAr) which regulates its own translation in cis. Here the authors show that GAr stimulates PI3Kδ-mediated induction of E2F1 translation, leading to c-Myc induction and stimulation of proliferation.
- Sivakumar Vadivel Gnanasundram
- , Slovénie Pyndiah
- & Robin Fåhraeus
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Article
| Open AccessSYK kinase mediates brown fat differentiation and activation
Spleen protein tyrosine kinase (Syk) has so far been mainly studied in haematopoietic and immune cells. Here, the authors show that Syk also has a role in brown adipose tissue, where it regulates the formation of brown adipocytes and their thermogenic activation in response to β-adrenergic stimulation.
- Marko Knoll
- , Sally Winther
- & Harvey F. Lodish
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Article
| Open AccessCTCF driven TERRA transcription facilitates completion of telomere DNA replication
TERRA RNA is involved in maintaining stability during telomere repeat replication. Here the authors, by using CRISPR/Cas9, mutate CTCF-binding sites at start site of TERRA transcripts and find that subtelomeric CTCF facilitates telomeric DNA replication by promoting TERRA transcription.
- Kate Beishline
- , Olga Vladimirova
- & Paul M. Lieberman
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