High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Cody J. Aros, Manash K. Paul, Carla J. Pantoja, Bharti Bisht, Luisa K. Meneses, Preethi Vijayaraj, Jenna M. Sandlin, Bryan France, Jonathan A. Tse, Michelle W. Chen, David W. Shia, Tammy M. Rickabaugh, Robert Damoiseaux, Brigitte N. GompertsSummaryMechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that β-catenin phosphorylated at Y489 (p-β-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of ai...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Rocco Lucero, Valentina Zappulli, Alessandro Sammarco, Oscar D. Murillo, Pike See Cheah, Srimeenakshi Srinivasan, Eric Tai, David T. Ting, Zhiyun Wei, Matthew E. Roth, Louise C. Laurent, Anna M. Krichevsky, Xandra O. Breakefield, Aleksandar MilosavljevicSummaryGlioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor micro...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Small Molecule Inhibition of GSK-3 Specifically Inhibits the Transcription of Inhibitory Co-receptor LAG-3 for Enhanced Anti-tumor Immunity
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Christopher E. Rudd, Kittiphat Chanthong, Alison TaylorSummaryImmune checkpoint blockade using antibodies against negative co-receptors such as cytolytic T cell antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has seen much success treating cancer. However, most patients are still not cured, underscoring the need for improved treatments and the possible development of small molecule inhibitors (SMIs) for improved immunotherapy. We previously showed that glycogen synthase kinase (GSK)-3α/β is a central regulator of PD-1...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Pulsatile MAPK Signaling Modulates p53 Activity to Control Cell Fate Decisions at the G2 Checkpoint for DNA Damage
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Siddharth De, Callum Campbell, Ashok R. Venkitaraman, Alessandro EspositoSummaryCell-autonomous changes in p53 expression govern the duration and outcome of cell-cycle arrest at the G2 checkpoint for DNA damage. Here, we report that mitogen-activated protein kinase (MAPK) signaling integrates extracellular cues with p53 dynamics to determine cell fate at the G2 checkpoint. Optogenetic tools and quantitative cell biochemistry reveal transient oscillations in MAPK activity dependent on ataxia-telangiectasia-mutated kinase after DNA damage. M...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Sen1 Is Recruited to Replication Forks via Ctf4 and Mrc1 and Promotes Genome Stability
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Rowin Appanah, Emma Claire Lones, Umberto Aiello, Domenico Libri, Giacomo De PiccoliSummaryDNA replication and RNA transcription compete for the same substrate during S phase. Cells have evolved several mechanisms to minimize such conflicts. Here, we identify the mechanism by which the transcription termination helicase Sen1 associates with replisomes. We show that the N terminus of Sen1 is both sufficient and necessary for replisome association and that it binds to the replisome via the components Ctf4 and Mrc1. We generated a separation ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

ELAC1 Repairs tRNAs Cleaved during Ribosome-Associated Quality Control
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Matthew C.J. Yip, Simonas Savickas, Steven P. Gygi, Sichen ShaoSummaryRibosome-associated quality control (RQC) disassembles aberrantly stalled translation complexes to recycle or degrade the constituent parts. A key step of RQC is the cleavage of P-site tRNA by the endonuclease ANKZF1 (Vms1 in yeast) to release incompletely synthesized polypeptides from ribosomes for degradation. Re-use of the cleaved tRNA for translation requires re-addition of the universal 3′CCA nucleotides removed by ANKZF1. Here, we show that ELAC1 is both...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Inhibitory Interactions and Columnar Inputs to an Object Motion Detector in Drosophila
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Mehmet F. Keleş, Ben J. Hardcastle, Carola Städele, Qi Xiao, Mark A. FryeSummaryThe direction-selective T4/T5 cells innervate optic-flow processing projection neurons in the lobula plate of the fly that mediate the visual control of locomotion. In the lobula, visual projection neurons coordinate complex behavioral responses to visual features, however, the input circuitry and computations that bestow their feature-detecting properties are less clear. Here, we study a highly specialized small object motion detector, LC11, and demonstr...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

A Dynamic Folded Hairpin Conformation Is Associated with α-Globin Activation in Erythroid Cells
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Andrea M. Chiariello, Simona Bianco, A. Marieke Oudelaar, Andrea Esposito, Carlo Annunziatella, Luca Fiorillo, Mattia Conte, Alfonso Corrado, Antonella Prisco, Martin S.C. Larke, Jelena M. Telenius, Renato Sciarretta, Francesco Musella, Veronica J. Buckle, Douglas R. Higgs, Jim R. Hughes, Mario NicodemiSummaryWe investigate the three-dimensional (3D) conformations of the α-globin locus at the single-allele level in murine embryonic stem cells (ESCs) and erythroid cells, combining polymer physics models and high-resolution Capture-C d...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

HIRA, a DiGeorge Syndrome Candidate Gene, Confers Proper Chromatin Accessibility on HSCs and Supports All Stages of Hematopoiesis
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Chao Chen, Ming-an Sun, Claude Warzecha, Mahesh Bachu, Anup Dey, Tiyun Wu, Peter D Adams, Todd Macfarlan, Paul Love, Keiko OzatoSummaryHIRA is a histone chaperone that deposits the histone variant H3.3 in transcriptionally active genes. In DiGeorge syndromes, a DNA stretch encompassing HIRA is deleted. The syndromes manifest varied abnormalities, including immunodeficiency and thrombocytopenia. HIRA is essential in mice, as total knockout (KO) results in early embryonic death. However, the role of HIRA in hematopoiesis is poorly understood...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Regulatory Dynamics of Tet1 and Oct4 Resolve Stages of Global DNA Demethylation and Transcriptomic Changes in Reprogramming
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Michela Bartoccetti, Bernard K. van der Veer, Xinlong Luo, Rita Khoueiry, Pinyi She, Manmohan Bajaj, Jiayi Xu, Adrian Janiszewski, Bernard Thienpont, Vincent Pasque, Kian Peng KohSummaryReprogramming somatic cells into induced pluripotent stem cells (iPSCs) involves the reactivation of endogenous pluripotency genes and global DNA demethylation, but temporal resolution of these events using existing markers is limited. Here, we generate murine transgenic lines harboring reporters for the 5-methylcytosine dioxygenase Tet1 and for Oct4. By mo...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

A Highly Conserved Circular RNA Is Required to Keep Neural Cells in a Progenitor State in the Mammalian Brain
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Christin Suenkel, Daniel Cavalli, Simone Massalini, Federico Calegari, Nikolaus RajewskySummarycircSLC45A4 is the main RNA splice isoform produced from its genetic locus and one of the highest expressed circRNAs in the developing human frontal cortex. Knockdown of this highly conserved circRNA in a human neuroblastoma cell line is sufficient to induce spontaneous neuronal differentiation, measurable by increased expression of neuronal marker genes. Depletion of circSlc45a4 in the developing mouse cortex causes a significant reduction ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Helen M. Melo, Gisele da S. Seixas da Silva, Marcella Ramos Sant’Ana, Camila Vieira Ligo Teixeira, Julia R. Clarke, Vivian S. Miya Coreixas, Bruno C. de Melo, Juliana T.S. Fortuna, Leticia Forny-Germano, José Henrique Ledo, Maíra S. Oliveira, Claudia P. Figueiredo, Raphaelle Pardossi-Piquard, Frédéric Checler, José María Delgado-García, Agnès Gruart, Licio A. Velloso, Marcio L.F. Balthazar, Dennys E. Cintra, Sergio T. FerreiraSummaryObesity has been associated with cognitive dec...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

STAT Signaling Modifies Ascl1 Chromatin Binding and Limits Neural Regeneration from Muller Glia in Adult Mouse Retina
In this study, we test whether injury-induced STAT activation hampers the ability of Ascl1 to reprogram MG into retinal neurons. Single-cell RNA-seq shows that progenitor-like cells derived from Ascl1-expressing MG have a higher level of STAT signaling than do those cells that become neurons. Ascl1-ChIPseq and ATAC-seq show that STAT potentially directs Ascl1 to developmentally inappropriate targets. Using a STAT inhibitor, in combination with our previously described reprogramming paradigm, we found a large increase in the ability of MG to generate neurons.Graphical Abstract (Source: Cell Reports)
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Kelly Mulfaul, Ema Ozaki, Nilisha Fernando, Kiva Brennan, Kathleen R. Chirco, Emma Connolly, Chris Greene, Arvydas Maminishkis, Robert G. Salomon, Mikhail Linetsky, Riccardo Natoli, Robert F. Mullins, Matthew Campbell, Sarah L. DoyleSummaryRetinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rat...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Leigh D. Plant, Dazhi Xiong, Jesus Romero, Hui Dai, Steve A.N. GoldsteinSummaryAcute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of sing...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

OTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Lien Verboom, Arne Martens, Dario Priem, Esther Hoste, Mozes Sze, Hanna Vikkula, Lisette Van Hove, Sofie Voet, Jana Roels, Jonathan Maelfait, Laura Bongiovanni, Alain de Bruin, Charlotte L. Scott, Yvan Saeys, Manolis Pasparakis, Mathieu J.M. Bertrand, Geert van LooSummaryInflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Vu Thuy Khanh Le-Trilling, Tanja Becker, Aharon Nachshon, Noam Stern-Ginossar, Lara Schöler, Sebastian Voigt, Hartmut Hengel, Mirko TrillingSummaryHuman cytomegalovirus (HCMV) causes diseases in individuals with immature or compromised immunity. To evade immune control, HCMV evolved numerous antagonists targeting the interferon system at multiple levels. By comparative analysis of naturally arising variants of the most widely studied HCMV strain, AD169, and a panel of targeted mutants, we uncover the UL145 gene as indispensable for ST...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Nef-Mediated CD3-TCR Downmodulation Dampens Acute Inflammation and Promotes SIV Immune Evasion
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Simone Joas, Ulrike Sauermann, Berit Roshani, Antonina Klippert, Maria Daskalaki, Kerstin Mätz-Rensing, Nicole Stolte-Leeb, Anke Heigele, Gregory K. Tharp, Prachi Mehrotra Gupta, Sydney Nelson, Steven Bosinger, Laura Parodi, Luis Giavedoni, Guido Silvestri, Daniel Sauter, Christiane Stahl-Hennig, Frank KirchhoffSummaryThe inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-med...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Genomic and Epidemiological Surveillance of Zika Virus in the Amazon Region
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Marta Giovanetti, Nuno Rodrigues Faria, José Lourenço, Jaqueline Goes de Jesus, Joilson Xavier, Ingra Morales Claro, Moritz U.G. Kraemer, Vagner Fonseca, Simon Dellicour, Julien Thézé, Flavia da Silva Salles, Tiago Gräf, Paola Paz Silveira, Valdinete Alves do Nascimento, Victor Costa de Souza, Felipe Campos de Melo Iani, Emerson Augusto Castilho-Martins, Laura Nogueira Cruz, Gabriel Wallau, Allison FabriSummaryZika virus (ZIKV) has caused an explosive epidemic linked to severe clinical outcomes in the Ameri...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

CD32+CD4+ T Cells Are Highly Enriched for HIV DNA and Can Support Transcriptional Latency
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Gilles Darcis, Neeltje A. Kootstra, Berend Hooibrink, Thijs van Montfort, Irma Maurer, Kevin Groen, Suzanne Jurriaans, Margreet Bakker, Carine van Lint, Ben Berkhout, Alexander O. PasternakSummaryThe HIV latent reservoir forms the major hurdle to an HIV cure. The discovery of CD32 as marker of this reservoir has aroused much interest, but subsequent reports have challenged this finding. Here, we observe a positive correlation between the percentages of CD32+ cells among CD4+ T cells of aviremic cART-treated, HIV-infected individuals a...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Propionic Acid Promotes the Virulent Phenotype of Crohn’s Disease-Associated Adherent-Invasive Escherichia coli
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Michael J. Ormsby, Síle A. Johnson, Nuria Carpena, Lynsey M. Meikle, Robert J. Goldstone, Anne McIntosh, Hannah M. Wessel, Heather E. Hulme, Ceilidh C. McConnachie, James P.R. Connolly, Andrew J. Roe, Conor Hasson, Joseph Boyd, Eamonn Fitzgerald, Konstantinos Gerasimidis, Douglas Morrison, Georgina L. Hold, Richard Hansen, Daniel Walker, David G.E. SmithSummaryPropionic acid (PA) is a bacterium-derived intestinal antimicrobial and immune modulator used widely in food production and agriculture. Passage of Crohn’s disease-assoc...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Francois Brial, Fawaz Alzaid, Kazuhiro Sonomura, Yoichiro Kamatani, Kelly Meneyrol, Aurélie Le Lay, Noémie Péan, Lyamine Hedjazi, Taka-Aki Sato, Nicolas Venteclef, Christophe Magnan, Mark Lathrop, Marc-Emmanuel Dumas, Fumihiko Matsuda, Pierre Zalloua, Dominique GauguierSummaryExposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

A High-Throughput Screening Identifies MICU1 Targeting Compounds
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Giulia Di Marco, Francesca Vallese, Benjamin Jourde, Christian Bergsdorf, Mattia Sturlese, Agnese De Mario, Valerie Techer-Etienne, Dorothea Haasen, Berndt Oberhauser, Simone Schleeger, Giulia Minetti, Stefano Moro, Rosario Rizzuto, Diego De Stefani, Mara Fornaro, Cristina MammucariSummaryMitochondrial Ca2+ uptake depends on the mitochondrial calcium uniporter (MCU) complex, a highly selective channel of the inner mitochondrial membrane (IMM). Here, we screen a library of 44,000 non-proprietary compounds for their ability to modulate mitoc...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer’s Disease-Related Models
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Alice Rossi, Giulia Rigotto, Giulia Valente, Valentina Giorgio, Emy Basso, Riccardo Filadi, Paola PizzoSummaryMitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer’s disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, m...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Topography in the Bursting Dynamics of Entorhinal Neurons
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Jason S. Bant, Kiah Hardcastle, Samuel A. Ocko, Lisa M. GiocomoSummaryMedial entorhinal cortex contains neural substrates for representing space. These substrates include grid cells that fire in repeating locations and increase in scale progressively along the dorsal-to-ventral entorhinal axis, with the physical distance between grid firing nodes increasing from tens of centimeters to several meters in rodents. Whether the temporal scale of grid cell spiking dynamics shows a similar dorsal-to-ventral organization remains unknown. Here, we ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Distinct Dorsal and Ventral Hippocampal CA3 Outputs Govern Contextual Fear Discrimination
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Antoine Besnard, Samara M. Miller, Amar SahaySummaryConsiderable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However, the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm, we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral ...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Charleen Salesse, Julien Charest, Hélène Doucet-Beaupré, Anne-Marie Castonguay, Simon Labrecque, Paul De Koninck, Martin LévesqueSummaryThe neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postm...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Guifen Wu, Manfred Schmid, Leonor Rib, Patrik Polak, Nicola Meola, Albin Sandelin, Torben Heick JensenSummaryDegradation of transcripts in human nuclei is primarily facilitated by the RNA exosome. To obtain substrate specificity, the exosome is aided by adaptors; in the nucleoplasm, those adaptors are the nuclear exosome-targeting (NEXT) complex and the poly(A) (pA) exosome-targeting (PAXT) connection. How these adaptors guide exosome targeting remains enigmatic. Employing high-resolution 3′ end sequencing, we demonstrate that N...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Mu-Yan Cai, Connor E. Dunn, Wenxu Chen, Bose S. Kochupurakkal, Huy Nguyen, Lisa A. Moreau, Geoffrey I. Shapiro, Kalindi Parmar, David Kozono, Alan D. D’AndreaSummaryCells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-w...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Physiological Tolerance to ssDNA Enables Strand Uncoupling during DNA Replication
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Amaia Ercilla, Jan Benada, Sampath Amitash, Gijs Zonderland, Giorgio Baldi, Kumar Somyajit, Fena Ochs, Vincenzo Costanzo, Jiri Lukas, Luis ToledoSummaryIt has been long assumed that normally leading strand synthesis must proceed coordinated with the lagging strand to prevent strand uncoupling and the pathological accumulation of single-stranded DNA (ssDNA) in the cell, a dogma recently challenged by in vitro studies in prokaryotes. Here, we report that human DNA polymerases can function independently at each strand in vivo and th...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Chaperone-Facilitated Aggregation of Thermo-Sensitive Proteins Shields Them from Degradation during Heat Stress
In conclusion, formation of PACs during heat shock is a chaperone-mediated adaptation strategy.Graphical Abstract (Source: Cell Reports)
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

CtBP1-Mediated Membrane Fission Contributes to Effective Recycling of Synaptic Vesicles
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Daniela Ivanova, Cordelia Imig, Marcial Camacho, Annika Reinhold, Debarpan Guhathakurta, Carolina Montenegro-Venegas, Michael A. Cousin, Eckart D. Gundelfinger, Christian Rosenmund, Benjamin Cooper, Anna FejtovaSummaryCompensatory endocytosis of released synaptic vesicles (SVs) relies on coordinated signaling at the lipid-protein interface. Here, we address the synaptic function of C-terminal binding protein 1 (CtBP1), a ubiquitous regulator of gene expression and membrane trafficking in cultured hippocampal neurons. In the absence of CtBP...
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Dezhi Zhao, Qian Zhang, Yiqi Liu, Xia Li, Kai Zhao, Yuanyuan Ding, Zhiqing Li, Qicong Shen, Chunmei Wang, Nan Li, Xuetao Cao (Source: Cell Reports)
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Control of Lipid Metabolism by Tachykinin in Drosophila
Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Wei Song, Jan A. Veenstra, Norbert Perrimon (Source: Cell Reports)
Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research

Partial Inhibition of RNA Polymerase I Promotes Animal Health and Longevity
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Guillermo Martínez Corrales, Danny Filer, Katharina C. Wenz, Abbie Rogan, George Phillips, Mengjia Li, Yodit Feseha, Susan J. Broughton, Nazif AlicSummaryHealth and survival in old age can be improved by changes in gene expression. RNA polymerase (Pol) I is the essential, conserved enzyme whose task is to generate the pre-ribosomal RNA (rRNA). We find that reducing the levels of Pol I activity is sufficient to extend lifespan in the fruit fly. This effect can be recapitulated by partial, adult-restricted inhibition, with both entero...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

NAD+ Repletion Rescues Female Fertility during Reproductive Aging
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Michael J. Bertoldo, Dave R. Listijono, Wing-Hong Jonathan Ho, Angelique H. Riepsamen, Dale M. Goss, Dulama Richani, Xing L. Jin, Saabah Mahbub, Jared M. Campbell, Abbas Habibalahi, Wei-Guo Nicholas Loh, Neil A. Youngson, Jayanthi Maniam, Ashley S.A. Wong, Kaisa Selesniemi, Sonia Bustamante, Catherine Li, Yiqing Zhao, Maria B. Marinova, Lynn-Jee KimSummaryReproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of o...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Synthetic Analyses of Single-Cell Transcriptomes from Multiple Brain Organoids and Fetal Brain
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Yoshiaki Tanaka, Bilal Cakir, Yangfei Xiang, Gareth J. Sullivan, In-Hyun ParkSummaryHuman brain organoid systems offer unprecedented opportunities to investigate both neurodevelopmental and neurological disease. Single-cell-based transcriptomics or epigenomics have dissected the cellular and molecular heterogeneity in the brain organoids, revealing a complex organization. Similar but distinct protocols from different labs have been applied to generate brain organoids, providing a large resource to perform a comparative analysis of&nbs...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

A Requirement for Argonaute 4 in Mammalian Antiviral Defense
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Fatemeh Adiliaghdam, Megha Basavappa, Tahnee L. Saunders, Dewi Harjanto, John T. Prior, D. Alexander Cronkite, Nina Papavasiliou, Kate L. JeffreySummaryWhile interferon (IFN) responses are critical for mammalian antiviral defense, induction of antiviral RNA interference (RNAi) is evident. To date, individual functions of the mammalian RNAi and micro RNA (miRNA) effector proteins Argonautes 1–4 (AGO1–AGO4) during virus infection remain undetermined. AGO2 was recently implicated in mammalian antiviral defense, so we examined anti...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Transcriptional Correlates of Tolerance and Lethality in Mice Predict Ebola Virus Disease Patient Outcomes
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Adam Price, Atsushi Okumura, Elaine Haddock, Friederike Feldmann, Kimberly Meade-White, Pryanka Sharma, Methinee Artami, W. Ian Lipkin, David W. Threadgill, Heinz Feldmann, Angela L. RasmussenSummaryHost response to infection is a major determinant of disease severity in Ebola virus disease (EVD), but gene expression programs associated with outcome are poorly characterized. Collaborative Cross (CC) mice develop strain-dependent EVD phenotypes of differential severity, ranging from tolerance to lethality. We screen 10 CC lines and identify...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab)
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Fernando Garces, Christopher Mohr, Li Zhang, Ching-Shin Huang, Qing Chen, Chadwick King, Cen Xu, Zhulun WangSummaryCalcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Aimovig (erenumab; erenumab-aooe in the United States) is the only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) therapy against the CGRP receptor (CGRPR) for the prevention of migraine. Aimovig is also the first FDA-approved mAb against a G-protein-coupled receptor (GPCR). Here, we report the architecture and functi...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

A Switch in Tissue Stem Cell Identity Causes Neuroendocrine Tumors in Drosophila Gut
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Zhaohui Li, Xingting Guo, Huanwei Huang, Chenhui Wang, Fu Yang, Yongchao Zhang, Jiawen Wang, Lu Han, Zhen Jin, Tao Cai, Rongwen XiSummaryIntestinal stem cells (ISCs) are able to generate gut-specific enterocytes, as well as neural-like enteroendocrine cells. It is unclear how the tissue identity of the ISC lineage is regulated to confer cell-lineage fidelity. Here, we show that, in adult Drosophila midgut, loss of the transcriptional repressor Tramtrack in ISCs causes a self-renewal program switch to neural stem cell (NSC)-like, and that s...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Laura Di Magno, Simona Manni, Fiorella Di Pastena, Sonia Coni, Alberto Macone, Sara Cairoli, Manolo Sambucci, Paola Infante, Marta Moretti, Marialaura Petroni, Carmine Nicoletti, Carlo Capalbo, Enrico De Smaele, Lucia Di Marcotullio, Giuseppe Giannini, Luca Battistini, Bianca Maria Goffredo, Egidio Iorio, Enzo Agostinelli, Marella MaroderSummaryThe antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinic...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Yan Li, Lisa Elmén, Igor Segota, Yibo Xian, Roberto Tinoco, Yongmei Feng, Yu Fujita, Rafael R. Segura Muñoz, Robert Schmaltz, Linda M. Bradley, Amanda Ramer-Tait, Raphy Zarecki, Tao Long, Scott N. Peterson, Ze’ev A. RonaiSummaryGrowing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor ...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Transcriptional Programs Define Intratumoral Heterogeneity of Ewing Sarcoma at Single-Cell Resolution
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Marie-Ming Aynaud, Olivier Mirabeau, Nadege Gruel, Sandrine Grossetête, Valentina Boeva, Simon Durand, Didier Surdez, Olivier Saulnier, Sakina Zaïdi, Svetlana Gribkova, Aziz Fouché, Ulykbek Kairov, Virginie Raynal, Franck Tirode, Thomas G.P. Grünewald, Mylene Bohec, Sylvain Baulande, Isabelle Janoueix-Lerosey, Jean-Philippe Vert, Emmanuel BarillotSummaryEWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive ...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Caihong Wang, Shaosen Zhang, Jie Liu, Yang Tian, Boyuan Ma, Siran Xu, Yan Fu, Yongzhang LuoSummaryCancer cell-derived secretomes have been documented to play critical roles in cancer progression. Intriguingly, alternative extracellular roles of intracellular proteins are involved in various steps of tumor progression, which can offer strategies to fight cancer. Herein, we identify lung cancer progression-associated secretome signatures using mass spectrometry analysis. Among them, PKM2 is verified to be highly expressed and secreted in lun...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Dynamic Imaging of LDH Inhibition in Tumors Reveals Rapid In Vivo Metabolic Rewiring and Vulnerability to Combination Therapy
We describe an LDHi with potent, on-target, in vivo activity. Using hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI), we demonstrate in vivo LDH inhibition in two glycolytic cancer models, MIA PaCa-2 and HT29, and we correlate depth and duration of LDH inhibition with direct anti-tumor activity. HP-MRSI also reveals a metabolic rewiring that occurs in vivo within 30 min of LDH inhibition, wherein pyruvate in a tumor is redirected toward mitochondrial metabolism. Using HP-MRSI, we show that inhibition of mitochondrial complex 1 rapidly redirects tumor pyruvate toward lactate. Inhibition ...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

HILPDA Uncouples Lipid Droplet Accumulation in Adipose Tissue Macrophages from Inflammation and Metabolic Dysregulation
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Xanthe A.M.H. van Dierendonck, Montserrat A. de la Rosa Rodriguez, Anastasia Georgiadi, Frits Mattijssen, Wieneke Dijk, Michel van Weeghel, Rajat Singh, Jan Willem Borst, Rinke Stienstra, Sander KerstenSummaryObesity leads to a state of chronic, low-grade inflammation that features the accumulation of lipid-laden macrophages in adipose tissue. Here, we determined the role of macrophage lipid-droplet accumulation in the development of obesity-induced adipose-tissue inflammation, using mice with myeloid-specific deficiency of the lipid-induc...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity
We report that TFE3 acts in a feedback loop to transcriptionally activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. Tfe3 deletion in Flcn knockout mice reduces the number of phagocytes and ameliorates LSD-like phenotypes. We further reveal that TFE3 stimulates glycogenesis by promoting the expression of glycogenesis genes, including Gys1 and Gyg, upon loss of Flcn. Taken together, we propose that the FLCN-TFE3 feedback loop acts as a rheostat to control lysosome activity and prevents excessive glycogenesis and LSD-like phagocyte activation.Graphical Abstract (Source: Cell Reports)
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Fangfang Sun, Yilie Liao, Xingfan Qu, Xia Xiao, Shaocong Hou, Zheqin Chen, Haipeng Huang, Pingping Li, Suneng FuSummaryNutrients stimulate the anabolic synthesis of proteins and lipids, but selective insulin resistance in obesity biases the anabolic program toward lipogenesis. Here, we report the identification of a DNAJB9-driven program that favors protein synthesis and energy production over lipid accumulation. We show there are two pools of DNAJB9 cochaperone. DNAJB9 in the ER lumen promotes the degradation of the lipogenic transcriptio...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research

Regulation of Nucleotide Metabolism and Germline Proliferation in Response to Nucleotide Imbalance and Genotoxic Stresses by EndoU Nuclease
Publication date: 11 February 2020Source: Cell Reports, Volume 30, Issue 6Author(s): Fan Jia, Congwu Chi, Min HanSummaryNucleotide deprivation and imbalance present detrimental conditions for animals and are thus expected to trigger cellular responses that direct protective changes in metabolic, developmental, and behavioral programs, albeit such mechanisms are vastly underexplored. Following our previous finding that Caenorhabditis elegans shut down germ cell proliferation in response to pyrimidine deprivation, we find in this study that endonuclease ENDU-2 regulates nucleotide metabolism and germ cell proliferation ...
Source: Cell Reports - February 13, 2020 Category: Cytology Source Type: research