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  • In case of stress, hold tight: phosphorylation switches PDI from an oxidoreductase to a holdase, tuning ER proteostasis
    EMBO J. (IF 11.227) Pub Date : 2020-04-02
    Joao PL Coelho; Matthias J Feige

    Eukaryotic cells have evolved multiple responses that allow endoplasmic reticulum (ER) homeostasis to be maintained even in the face of acute or chronic stresses. In this issue, Yu et al (2020) describe how site‐specific phosphorylation switches protein disulfide isomerase (PDI) from a folding enzyme to a holdase chaperone which regulates ER stress responses, thus highlighting PDI as a key player in

  • RAD51 discrimination between single- and double-strand DNA: a matter of flexibility and enthalpy.
    EMBO J. (IF 11.227) Pub Date : 2020-02-24
    Shyamal Subramanyam,Maria Spies

    In selecting ssDNA over dsDNA, the RAD51 DNA strand exchange protein has to overcome the entropy associated with straightening of single-strand DNA upon nucleoprotein filament formation. New work in The EMBO Journal (Paoletti et al, 2020), combined biophysical analysis of the RAD51-ssDNA interaction with mathematical modeling to show that the flexibility of DNA positively correlates with nucleation

  • Molecular flexibility of DNA as a key determinant of RAD51 recruitment.
    EMBO J. (IF 11.227) Pub Date : 2020-01-14
    Federico Paoletti,Afaf H El-Sagheer,Jun Allard,Tom Brown,Omer Dushek,Fumiko Esashi

    The timely activation of homologous recombination is essential for the maintenance of genome stability, in which the RAD51 recombinase plays a central role. Biochemically, human RAD51 polymerises faster on single-stranded DNA (ssDNA) compared to double-stranded DNA (dsDNA), raising a key conceptual question: how does it discriminate between them? In this study, we tackled this problem by systematically

  • SMCHD1 promotes ATM-dependent DNA damage signaling and repair of uncapped telomeres.
    EMBO J. (IF 11.227) Pub Date : 2020-02-21
    Aleksandra Vančevska,Wareed Ahmed,Verena Pfeiffer,Marianna Feretzaki,Simon J Boulton,Joachim Lingner

    Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1) has been implicated in X-chromosome inactivation, imprinting, and DNA damage repair, and mutations in SMCHD1 can cause facioscapulohumeral muscular dystrophy. More recently, SMCHD1 has also been identified as a component of telomeric chromatin. Here, we report that SMCHD1 is required for DNA damage signaling and

  • Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells.
    EMBO J. (IF 11.227) Pub Date : 2020-03-03
    Yoshiki Higashijima,Yusuke Matsui,Teppei Shimamura,Ryo Nakaki,Nao Nagai,Shuichi Tsutsumi,Yohei Abe,Verena M Link,Mizuko Osaka,Masayuki Yoshida,Ryo Watanabe,Toshihiro Tanaka,Akashi Taguchi,Mai Miura,Xiaoan Ruan,Guoliang Li,Tsuyoshi Inoue,Masaomi Nangaku,Hiroshi Kimura,Tetsushi Furukawa,Hiroyuki Aburatani,Youichiro Wada,Yijun Ruan,Christopher K Glass,Yasuharu Kanki

    Histone H3 lysine-9 di-methylation (H3K9me2) and lysine-27 tri-methylation (H3K27me3) are linked to repression of gene expression, but the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. Here, we report that lysine demethylases 7A (KDM7A) and 6A (UTX) play crucial roles in tumor necrosis factor (TNF)-α signaling in endothelial cells (ECs), where

  • A plant-specific SWR1 chromatin-remodeling complex couples histone H2A.Z deposition with nucleosome sliding.
    EMBO J. (IF 11.227) Pub Date : 2020-03-02
    Yu-Xi Luo,Xiao-Mei Hou,Cui-Jun Zhang,Lian-Mei Tan,Chang-Rong Shao,Rong-Nan Lin,Yin-Na Su,Xue-Wei Cai,Lin Li,She Chen,Xin-Jian He

    Deposition of H2A.Z in chromatin is known to be mediated by a conserved SWR1 chromatin-remodeling complex in eukaryotes. However, little is known about whether and how the SWR1 complex cooperates with other chromatin regulators. Using immunoprecipitation followed by mass spectrometry, we found all known components of the Arabidopsis thaliana SWR1 complex and additionally identified the following three

  • Termination of non-coding transcription in yeast relies on both an RNA Pol II CTD interaction domain and a CTD-mimicking region in Sen1.
    EMBO J. (IF 11.227) Pub Date : 2020-02-28
    Zhong Han,Olga Jasnovidova,Nouhou Haidara,Agnieszka Tudek,Karel Kubicek,Domenico Libri,Richard Stefl,Odil Porrua

    Pervasive transcription is a widespread phenomenon leading to the production of a plethora of non-coding RNAs (ncRNAs) without apparent function. Pervasive transcription poses a threat to proper gene expression that needs to be controlled. In yeast, the highly conserved helicase Sen1 restricts pervasive transcription by inducing termination of non-coding transcription. However, the mechanisms underlying

  • Structural basis for centromere maintenance by Drosophila CENP‐A chaperone CAL1
    EMBO J. (IF 11.227) Pub Date : 2020-03-05
    Bethan Medina‐Pritchard; Vasiliki Lazou; Juan Zou; Olwyn Byron; Maria A Abad; Juri Rappsilber; Patrick Heun; A Arockia Jeyaprakash

    Centromeres are microtubule attachment sites on chromosomes defined by the enrichment of histone variant CENP‐A‐containing nucleosomes. To preserve centromere identity, CENP‐A must be escorted to centromeres by a CENP‐A‐specific chaperone for deposition. Despite this essential requirement, many eukaryotes differ in the composition of players involved in centromere maintenance, highlighting the plasticity

  • Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation.
    EMBO J. (IF 11.227) Pub Date : 2020-02-27
    Yexian Yuan,Pingwen Xu,Qingyan Jiang,Xingcai Cai,Tao Wang,Wentong Peng,Jiajie Sun,Canjun Zhu,Cha Zhang,Dong Yue,Zhihui He,Jinping Yang,Yuxian Zeng,Man Du,Fenglin Zhang,Lucas Ibrahimi,Sarah Schaul,Yuwei Jiang,Jiqiu Wang,Jia Sun,Qiaoping Wang,Liming Liu,Songbo Wang,Lina Wang,Xiaotong Zhu,Ping Gao,Qianyun Xi,Cong Yin,Fan Li,Guli Xu,Yongliang Zhang,Gang Shu

    Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation

  • Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling.
    EMBO J. (IF 11.227) Pub Date : 2020-03-04
    Jiuzhi Xu,Yang Tang,Xiaole Sheng,Yuhua Tian,Min Deng,Sujuan Du,Cong Lv,Guili Li,Yuwei Pan,Yongli Song,Pengbo Lou,Yongting Luo,Yuan Li,Bing Zhang,Yanmei Chen,Zhanju Liu,Yingzi Cong,Maksim V Plikus,Qingyong Meng,Zhaocai Zhou,Zhengquan Yu

    The Hippo-YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma-epithelium ISLR-YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal

  • Neurexins cluster Ca2+ channels within the presynaptic active zone
    EMBO J. (IF 11.227) Pub Date : 2020-03-05
    Fujun Luo; Alessandra Sclip; Man Jiang; Thomas C Südhof

    To achieve ultrafast neurotransmission, neurons assemble synapses with highly organized presynaptic and postsynaptic nanomachines that are aligned by synaptic adhesion molecules. How functional assembly of presynaptic active zones is controlled via trans‐synaptic interactions remains unknown. Here, we conditionally deleted all three neurexin adhesion molecules from presynaptic neurons of the calyx

  • Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues
    EMBO J. (IF 11.227) Pub Date : 2020-04-01
    Bert Houben; Emiel Michiels; Meine Ramakers; Katerina Konstantoulea; Nikolaos Louros; Joffré Verniers; Rob van der Kant; Matthias De Vleeschouwer; Nuno Chicória; Thomas Vanpoucke; Rodrigo Gallardo; Joost Schymkowitz; Frederic Rousseau

    Many chaperones favour binding to hydrophobic sequences that are flanked by basic residues while disfavouring acidic residues. However, the origin of this bias in protein quality control remains poorly understood. Here, we show that while acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure than basic amino acids. As a result,

  • Blocking the road to de‐differentiation: HNF1A/KDM6A complex safeguards epithelial integrity in pancreatic cancer
    EMBO J. (IF 11.227) Pub Date : 2020-04-01
    Stefanie Bärthel; Günter Schneider; Dieter Saur

    Epithelial differentiation of normal and tumor cells is orchestrated by lineage‐determining transcriptional regulatory networks that enforce cell identity. Recent research by Kalisz et al (2020) in the EMBO Journal elucidates the molecular mechanisms by which a transcriptional differentiation program governed by HNF1A and KDM6A maintains acinar differentiation and the epithelial identity of pancreatic

  • Grad‐seq in a Gram‐positive bacterium reveals exonucleolytic sRNA activation in competence control
    EMBO J. (IF 11.227) Pub Date : 2020-03-30
    Jens Hör; Geneviève Garriss; Silvia Di Giorgio; Lisa‐Marie Hack; Jens T Vanselow; Konrad U Förstner; Andreas Schlosser; Birgitta Henriques‐Normark; Jörg Vogel

    RNA–protein interactions are the crucial basis for many steps of bacterial gene expression, including post‐transcriptional control by small regulatory RNAs (sRNAs). In stark contrast to recent progress in the analysis of Gram‐negative bacteria, knowledge about RNA–protein complexes in Gram‐positive species remains scarce. Here, we used the Grad‐seq approach to draft a comprehensive landscape of such

  • Cyclin B1 scaffolds MAD1 at the kinetochore corona to activate the mitotic checkpoint
    EMBO J. (IF 11.227) Pub Date : 2020-03-23
    Lindsey A Allan; Magda Camacho Reis; Giuseppe Ciossani; Pim J Huis in ‘t Veld; Sabine Wohlgemuth; Geert JPL Kops; Andrea Musacchio; Adrian T Saurin

    Cyclin B:CDK1 is the master kinase regulator of mitosis. We show here that, in addition to its kinase functions, mammalian Cyclin B also scaffolds a localised signalling pathway to help preserve genome stability. Cyclin B1 localises to an expanded region of the outer kinetochore, known as the corona, where it scaffolds the spindle assembly checkpoint (SAC) machinery by binding directly to MAD1. In

  • Geranylgeranyl generosity: a new prenyl‐transferase gives a fat to a SNARE protein
    EMBO J. (IF 11.227) Pub Date : 2020-03-23
    Amy F Roth; Nicholas G Davis

    Protein prenylation, a well‐defined protein consensus motifs direct modification by one of three prenyl‐transferases, has been an area of fairly settled science for 20 or 30 years. Protein prenylation, the specific prenyl modification (farnesyl or geranylgeranyl), as well as the prenyl‐transferases involved can be inferred by protein sequence. Two new papers now upset this settled wisdom with the discovery

  • A guide to naming human non-coding RNA genes.
    EMBO J. (IF 11.227) Pub Date : 2020-02-24
    Ruth L Seal,Ling-Ling Chen,Sam Griffiths-Jones,Todd M Lowe,Michael B Mathews,Dawn O'Reilly,Andrew J Pierce,Peter F Stadler,Igor Ulitsky,Sandra L Wolin,Elspeth A Bruford

    Research on non-coding RNA (ncRNA) is a rapidly expanding field. Providing an official gene symbol and name to ncRNA genes brings order to otherwise potential chaos as it allows unambiguous communication about each gene. The HUGO Gene Nomenclature Committee (HGNC, www.genenames.org) is the only group with the authority to approve symbols for human genes. The HGNC works with specialist advisors for

  • SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport.
    EMBO J. (IF 11.227) Pub Date : 2020-02-21
    Marlieke Lm Jongsma,Jeroen Bakker,Birol Cabukusta,Nalan Liv,Daphne van Elsland,Job Fermie,Jimmy Ll Akkermans,Coenraad Kuijl,Sabina Y van der Zanden,Lennert Janssen,Denise Hoogzaad,Rik van der Kant,Ruud H Wijdeven,Judith Klumperman,Ilana Berlin,Jacques Neefjes

    The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by small membrane-bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to

  • Axonal precursor miRNAs hitchhike on endosomes and locally regulate the development of neural circuits.
    EMBO J. (IF 11.227) Pub Date : 2020-02-19
    Eloina Corradi,Irene Dalla Costa,Antoneta Gavoci,Archana Iyer,Michela Roccuzzo,Tegan A Otto,Eleonora Oliani,Simone Bridi,Stephanie Strohbuecker,Gabriela Santos-Rodriguez,Donatella Valdembri,Guido Serini,Cei Abreu-Goodger,Marie-Laure Baudet

    Various species of non-coding RNAs (ncRNAs) are enriched in specific subcellular compartments, but the mechanisms orchestrating their localization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre-miRNAs) are actively trafficked

  • Excessive excision of correct nucleotides during DNA synthesis explained by replication hurdles.
    EMBO J. (IF 11.227) Pub Date : 2020-02-09
    Anupam Singh,Manjula Pandey,Divya Nandakumar,Kevin D Raney,Y Whitney Yin,Smita S Patel

    The proofreading exonuclease activity of replicative DNA polymerase excises misincorporated nucleotides during DNA synthesis, but these events are rare. Therefore, we were surprised to find that T7 replisome excised nearly 7% of correctly incorporated nucleotides during leading and lagging strand syntheses. Similar observations with two other DNA polymerases establish its generality. We show that excessive

  • Local rewiring of genome-nuclear lamina interactions by transcription.
    EMBO J. (IF 11.227) Pub Date : 2020-02-21
    Laura Brueckner,Peiyao A Zhao,Tom van Schaik,Christ Leemans,Jiao Sima,Daniel Peric-Hupkes,David M Gilbert,Bas van Steensel

    Transcriptionally inactive genes are often positioned at the nuclear lamina (NL), as part of large lamina-associated domains (LADs). Activation of such genes is often accompanied by repositioning toward the nuclear interior. How this process works and how it impacts flanking chromosomal regions are poorly understood. We addressed these questions by systematic activation or inactivation of individual

  • Small RNA-binding protein RapZ mediates cell envelope precursor sensing and signaling in Escherichia coli.
    EMBO J. (IF 11.227) Pub Date : 2020-02-17
    Muna A Khan,Svetlana Durica-Mitic,Yvonne Göpel,Ralf Heermann,Boris Görke

    The RNA-binding protein RapZ cooperates with small RNAs (sRNAs) GlmY and GlmZ to regulate the glmS mRNA in Escherichia coli. Enzyme GlmS synthesizes glucosamine-6-phosphate (GlcN6P), initiating cell envelope biosynthesis. GlmZ activates glmS expression by base-pairing. When GlcN6P is ample, GlmZ is bound by RapZ and degraded through ribonuclease recruitment. Upon GlcN6P depletion, the decoy sRNA GlmY

  • The SiaA/B/C/D signaling network regulates biofilm formation in Pseudomonas aeruginosa.
    EMBO J. (IF 11.227) Pub Date : 2020-02-24
    Gukui Chen,Jianhua Gan,Chun Yang,Yili Zuo,Juan Peng,Meng Li,Weiping Huo,Yingpeng Xie,Yani Zhang,Tietao Wang,Xin Deng,Haihua Liang

    Bacterial cyclic-di-GMP (c-di-GMP) production is associated with biofilm development and the switch from acute to chronic infections. In Pseudomonas aeruginosa, the diguanylate cyclase (DGC) SiaD and phosphatase SiaA, which are co-transcribed as part of a siaABCD operon, are essential for cellular aggregation. However, the detailed functions of this operon and the relationships among its constituent

  • GT1b functions as a novel endogenous agonist of toll-like receptor 2 inducing neuropathic pain.
    EMBO J. (IF 11.227) Pub Date : 2020-02-06
    Hyoungsub Lim,Jaesung Lee,Byunghyun You,Jae Hoon Oh,Hyuck Jun Mok,Yoo Sung Kim,Bo-Eun Yoon,Byung Gon Kim,Seung Keun Back,Jong-Sang Park,Kwang Pyo Kim,Ronald L Schnaar,Sung Joong Lee

    Spinal cord microglia contribute to nerve injury-induced neuropathic pain. We have previously demonstrated that toll-like receptor 2 (TLR2) signaling is critical for nerve injury-induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury-induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to

  • Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment.
    EMBO J. (IF 11.227) Pub Date : 2020-02-03
    Karen Hoffmann,Hilmar Berger,Hagen Kulbe,Sukanija Thillainadarasan,Hans-Joachim Mollenkopf,Tomasz Zemojtel,Eliane Taube,Silvia Darb-Esfahani,Mandy Mangler,Jalid Sehouli,Radoslav Chekerov,Elena I Braicu,Thomas F Meyer,Mirjana Kessler

    High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the

  • ATM‐CHK2‐Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress
    EMBO J. (IF 11.227) Pub Date : 2020-03-18
    Qi‐Qiang Guo; Shan‐Shan Wang; Shan‐Shan Zhang; Hong‐De Xu; Xiao‐Man Li; Yi Guan; Fei Yi; Ting‐Ting Zhou; Bo Jiang; Ning Bai; Meng‐Tao Ma; Zhuo Wang; Yan‐Ling Feng; Wen‐Dong Guo; Xuan Wu; Gui‐Feng Zhao; Guang‐Jian Fan; Sheng‐Ping Zhang; Chuan‐Gui Wang; Long‐Yue Cao; Brian P O'Rourke; Shi‐Hui Liu; Ping‐Yuan Wang; Shuai Han; Xiao‐Yu Song; Liu Cao

    The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell

  • SCHENGEN receptor module drives localized ROS production and lignification in plant roots
    EMBO J. (IF 11.227) Pub Date : 2020-03-18
    Satoshi Fujita; Damien De Bellis; Kai H Edel; Philipp Köster; Tonni Grube Andersen; Emanuel Schmid‐Siegert; Valérie Dénervaud Tendon; Alexandre Pfister; Peter Marhavý; Robertas Ursache; Verónica G Doblas; Marie Barberon; Jean Daraspe; Audrey Creff; Gwyneth Ingram; Jörg Kudla; Niko Geldner

    Production of reactive oxygen species (ROS) by NADPH oxidases (NOXs) impacts many processes in animals and plants, and many plant receptor pathways involve rapid, NOX‐dependent increases of ROS. Yet, their general reactivity has made it challenging to pinpoint the precise role and immediate molecular action of ROS. A well‐understood ROS action in plants is to provide the co‐substrate for lignin peroxidases

  • Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS/FTD
    EMBO J. (IF 11.227) Pub Date : 2020-03-16
    Bahram Khosravi; Kathrine D LaClair; Henrick Riemenschneider; Qihui Zhou; Frédéric Frottin; Nikola Mareljic; Mareike Czuppa; Daniel Farny; Hannelore Hartmann; Meike Michaelsen; Thomas Arzberger; F Ulrich Hartl; Mark S Hipp; Dieter Edbauer

    The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72‐specific pathology and TDP‐43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly‐GA

  • Temporal specificity and heterogeneity of Drosophila immune cells
    EMBO J. (IF 11.227) Pub Date : 2020-03-12
    Pierre B Cattenoz; Rosy Sakr; Alexia Pavlidaki; Claude Delaporte; Andrea Riba; Nacho Molina; Nivedita Hariharan; Tina Mukherjee; Angela Giangrande

    Immune cells provide defense against non‐self and have recently been shown to also play key roles in diverse processes such as development, metabolism, and tumor progression. The heterogeneity of Drosophila immune cells (hemocytes) remains an open question. Using bulk RNA sequencing, we find that the hemocytes display distinct features in the embryo, a closed and rapidly developing system, compared

  • Alterations of redox and iron metabolism accompany the development of HIV latency
    EMBO J. (IF 11.227) Pub Date : 2020-03-11
    Iart Luca Shytaj; Bojana Lucic; Mattia Forcato; Carlotta Penzo; James Billingsley; Vibor Laketa; Steven Bosinger; Mia Stanic; Francesco Gregoretti; Laura Antonelli; Gennaro Oliva; Christian K Frese; Aleksandra Trifunovic; Bruno Galy; Clarissa Eibl; Guido Silvestri; Silvio Bicciato; Andrea Savarino; Marina Lusic

    HIV‐1 persists in a latent form during antiretroviral therapy, mainly in CD4+ T cells, thus hampering efforts for a cure. HIV‐1 infection is accompanied by metabolic alterations, such as oxidative stress, but the effect of cellular antioxidant responses on viral replication and latency is unknown. Here, we show that cells survive retroviral replication, both in vitro and in vivo in SIVmac‐infected

  • Light‐responsive microRNA miR‐211 targets Ezrin to modulate lysosomal biogenesis and retinal cell clearance
    EMBO J. (IF 11.227) Pub Date : 2020-03-10
    Federica Naso; Daniela Intartaglia; Danila Falanga; Chiara Soldati; Elena Polishchuk; Giuliana Giamundo; Paola Tiberi; Elena Marrocco; Paolo Scudieri; Chiara Di Malta; Ivana Trapani; Edoardo Nusco; Francesco Giuseppe Salierno; Enrico Maria Surace; Luis JV Galietta; Sandro Banfi; Alberto Auricchio; Andrea Ballabio; Diego Luis Medina; Ivan Conte

    Vertebrate vision relies on the daily phagocytosis and lysosomal degradation of photoreceptor outer segments (POS) within the retinal pigment epithelium (RPE). However, how these events are controlled by light is largely unknown. Here, we show that the light‐responsive miR‐211 controls lysosomal biogenesis at the beginning of light–dark transitions in the RPE by targeting Ezrin, a cytoskeleton‐associated

  • HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
    EMBO J. (IF 11.227) Pub Date : 2020-03-10
    Mark Kalisz; Edgar Bernardo; Anthony Beucher; Miguel Angel Maestro; Natalia del Pozo; Irene Millán; Lena Haeberle; Martin Schlensog; Sami Alexander Safi; Wolfram Trudo Knoefel; Vanessa Grau; Matías de Vas; Karl B Shpargel; Eva Vaquero; Terry Magnuson; Sagrario Ortega; Irene Esposito; Francisco X Real; Jorge Ferrer

    Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine‐specific demethylase 6A, carries somatic mutations in PDAC. Here,

  • CLUH granules coordinate translation of mitochondrial proteins with mTORC1 signaling and mitophagy
    EMBO J. (IF 11.227) Pub Date : 2020-03-09
    David Pla‐Martín; Désirée Schatton; Janica L Wiederstein; Marie‐Charlotte Marx; Salim Khiati; Marcus Krüger; Elena I Rugarli

    Mitochondria house anabolic and catabolic processes that must be balanced and adjusted to meet cellular demands. The RNA‐binding protein CLUH (clustered mitochondria homolog) binds mRNAs of nuclear‐encoded mitochondrial proteins and is highly expressed in the liver, where it regulates metabolic plasticity. Here, we show that in primary hepatocytes, CLUH coalesces in specific ribonucleoprotein particles

  • Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent.
    EMBO J. (IF 11.227) Pub Date : 2019-10-14
    Dane M Wolf,Mayuko Segawa,Arun Kumar Kondadi,Ruchika Anand,Sean T Bailey,Andreas S Reichert,Alexander M van der Bliek,David B Shackelford,Marc Liesa,Orian S Shirihai
  • Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments.
    EMBO J. (IF 11.227) Pub Date : 2019-07-01
    Sinan Kilic,Aleksandra Lezaja,Marco Gatti,Eliana Bianco,Jone Michelena,Ralph Imhof,Matthias Altmeyer
  • Xenograft and organoid model systems in cancer research.
    EMBO J. (IF 11.227) Pub Date : 2019-07-08
    Margit Bleijs,Marc van de Wetering,Hans Clevers,Jarno Drost

    Patient-derived tumour xenografts and tumour organoids have become important preclinical model systems for cancer research. Both models maintain key features from their parental tumours, such as genetic and phenotypic heterogeneity, which allows them to be used for a wide spectrum of applications. In contrast to patient-derived xenografts, organoids can be established and expanded with high efficiency

  • Microglial subtypes: diversity within the microglial community.
    EMBO J. (IF 11.227) Pub Date : 2019-08-02
    Vassilis Stratoulias,Jose Luis Venero,Marie-Ève Tremblay,Bertrand Joseph
  • Long-term expanding human airway organoids for disease modeling.
    EMBO J. (IF 11.227) Pub Date : 2019-01-14
    Norman Sachs,Angelos Papaspyropoulos,Domenique D Zomer-van Ommen,Inha Heo,Lena Böttinger,Dymph Klay,Fleur Weeber,Guizela Huelsz-Prince,Nino Iakobachvili,Gimano D Amatngalim,Joep de Ligt,Arne van Hoeck,Natalie Proost,Marco C Viveen,Anna Lyubimova,Luc Teeven,Sepideh Derakhshan,Jeroen Korving,Harry Begthel,Johanna F Dekkers,Kuldeep Kumawat,Emilio Ramos,Matthijs Fm van Oosterhout,G Johan Offerhaus,Dominique
  • Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death.
    EMBO J. (IF 11.227) Pub Date : 2019-09-23
    Hui Jiang,Xiaoyu Xue,Swarupa Panda,Ajinkya Kawale,Richard M Hooy,Fengshan Liang,Jungsan Sohn,Patrick Sung,Nelson O Gekara
  • Human Fis1 regulates mitochondrial dynamics through inhibition of the fusion machinery.
    EMBO J. (IF 11.227) Pub Date : 2019-03-06
    Rong Yu,Shao-Bo Jin,Urban Lendahl,Monica Nistér,Jian Zhao
  • Endosome and Golgi-associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism.
    EMBO J. (IF 11.227) Pub Date : 2019-05-27
    Oliver Schmidt,Yannick Weyer,Verena Baumann,Michael A Widerin,Sebastian Eising,Mihaela Angelova,Alexander Schleiffer,Leopold Kremser,Herbert Lindner,Matthias Peter,Florian Fröhlich,David Teis
  • Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress
    EMBO J. (IF 11.227) Pub Date : 2020-03-09
    Jiaojiao Yu; Tao Li; Yu Liu; Xi Wang; Jianchao Zhang; Xi'e Wang; Guizhi Shi; Jizhong Lou; Likun Wang; Chih‐chen Wang; Lei Wang

    Accumulated unfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR) to increase ER protein folding capacity. ER proteostasis and UPR signaling need to be regulated in a precise and timely manner. Here, we identify phosphorylation of protein disulfide isomerase (PDI), one of the most abundant and critical folding catalysts in the ER, as an early event during ER

  • Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation
    EMBO J. (IF 11.227) Pub Date : 2020-03-09
    Cristina Porcheri; Ohad Golan; Fernando J Calero‐Nieto; Roshana Thambyrajah; Cristina Ruiz‐Herguido; Xiaonan Wang; Francesca Catto; Yolanda Guillén; Roshani Sinha; Jessica González; Sarah J Kinston; Samanta A Mariani; Antonio Maglitto; Chris S Vink; Elaine Dzierzak; Pierre Charbord; Bertie Göttgens; Lluis Espinosa; David Sprinzak; Anna Bigas

    Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three‐dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic

  • Infection‐driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis in epithelial cells
    EMBO J. (IF 11.227) Pub Date : 2020-03-05
    Benoit Maffei; Marc Laverrière; Yongzheng Wu; Sébastien Triboulet; Stéphanie Perrinet; Magalie Duchateau; Mariette Matondo; Robert L Hollis; Charlie Gourley; Jan Rupp; Jeffrey W Keillor; Agathe Subtil

    Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme with transamidating activity. We report here that both expression and activity of TG2 are enhanced in mammalian epithelial cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 impairs bacterial development. We show that TG2 increases glucose import by up‐regulating the

  • Loss of salt tolerance during tomato domestication conferred by variation in a Na+/K+ transporter
    EMBO J. (IF 11.227) Pub Date : 2020-03-05
    Zhen Wang; Yechun Hong; Guangtao Zhu; Yumei Li; Qingfeng Niu; Juanjuan Yao; Kai Hua; Jinjuan Bai; Yingfang Zhu; Huazhong Shi; Sanwen Huang; Jian‐Kang Zhu

    Domestication has resulted in reduced salt tolerance in tomato. To identify the genetic components causing this deficiency, we performed a genome‐wide association study (GWAS) for root Na+/K+ ratio in a population consisting of 369 tomato accessions with large natural variations. The most significant variations associated with root Na+/K+ ratio were identified within the gene SlHAK20 encoding a member

  • Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress
    EMBO J. (IF 11.227) Pub Date : 2020-03-05
    Simon Schwörer; Mirela Berisa; Sara Violante; Weige Qin; Jiajun Zhu; Ronald C Hendrickson; Justin R Cross; Craig B Thompson

    The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor‐beta (TGFβ) play a critical role in wound healing. How TGFβ supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFβ promotes protein translation at least in part by increasing the mitochondrial oxidation of glucose and glutamine carbons to

  • A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus.
    EMBO J. (IF 11.227) Pub Date : 2020-03-03
    Ryutaro Shirakawa,Sakurako Goto-Ito,Kota Goto,Shonosuke Wakayama,Haremaru Kubo,Natsumi Sakata,Duc Anh Trinh,Atsushi Yamagata,Yusuke Sato,Hiroshi Masumoto,Jinglei Cheng,Toyoshi Fujimoto,Shuya Fukai,Hisanori Horiuchi

    Protein prenylation is essential for many cellular processes including signal transduction, cytoskeletal reorganization, and membrane trafficking. Here, we identify a novel type of protein prenyltransferase, which we named geranylgeranyltransferase type-III (GGTase-III). GGTase-III consists of prenyltransferase alpha subunit repeat containing 1 (PTAR1) and the β subunit of RabGGTase. Using a biotinylated

  • Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration.
    EMBO J. (IF 11.227) Pub Date : 2020-03-02
    Stefanie Weinert,Niclas Gimber,Dorothea Deuschel,Till Stuhlmann,Dmytro Puchkov,Zohreh Farsi,Carmen F Ludwig,Gaia Novarino,Karen I López-Cayuqueo,Rosa Planells-Cases,Thomas J Jentsch

    CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl- concentration. Disruption of endosomal ClC-3 causes severe neurodegeneration. To assess the importance of ClC-3 Cl- /H+ exchange, we now generate Clcn3unc/unc mice in which ClC-3 is converted into a Cl- channel. Unlike Clcn3-/- mice, Clcn3unc/unc mice appear normal owing to compensation by ClC-4 with

  • Beating the ER: novel insights into FAM134B function and regulation.
    EMBO J. (IF 11.227) Pub Date : 2020-02-19
    Chiara De Leonibus,Laura Cinque,Carmine Settembre

    To maintain cellular homeostasis, the endoplasmic reticulum (ER) necessitates a continuous removal of ER fragments via a selective, receptor-mediated, form of autophagy known as ER-phagy. In this issue of The EMBO Journal, Jiang et al (2020) shed light on how the best characterized autophagy receptor FAM134B mediates ER membrane fragmentation, the earliest event during ER-phagy. They propose a dynamic

  • Cytoskeletal tension actively sustains the migratory T-cell synaptic contact.
    EMBO J. (IF 11.227) Pub Date : 2020-01-02
    Sudha Kumari,Michael Mak,Yeh-Chuin Poh,Mira Tohme,Nicki Watson,Mariane Melo,Erin Janssen,Michael Dustin,Raif Geha,Darrell J Irvine

    When migratory T cells encounter antigen-presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T-cell immunity. While the cellular processes underlying synapse formation have been well characterized, those that maintain the symmetry, and thereby

  • FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Xiao Jiang,Xinyi Wang,Xianming Ding,Mengjie Du,Boran Li,Xialian Weng,Jingzi Zhang,Lin Li,Rui Tian,Qi Zhu,She Chen,Liang Wang,Wei Liu,Lei Fang,Dante Neculai,Qiming Sun

    Degradation of endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required

  • UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism.
    EMBO J. (IF 11.227) Pub Date : 2020-01-23
    Xing Feng,Dong Ma,Jiabao Zhao,Yongxi Song,Yuekun Zhu,Qingxin Zhou,Fei Ma,Xing Liu,Mengya Zhong,Yu Liu,Yubo Xiong,Xingfeng Qiu,Zhen Zhang,Heng Zhang,Yongxiang Zhao,Kaiguang Zhang,Xuehui Hong,Zhiyong Zhang

    UHMK1 is a nuclear serine/threonine kinase recently implicated in carcinogenesis. However, the functions and action mechanisms of UHMK1 in the pathogenesis of human gastric cancer (GC) are unclear. Here, we observed that UHMK1 was markedly upregulated in GC. UHMK1 silencing strongly inhibited GC aggressiveness. Interestingly, UHMK1-induced GC progression was mediated primarily via enhancing de novo

  • Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone.
    EMBO J. (IF 11.227) Pub Date : 2020-02-03
    Jun Wu,Wen-Jia Tian,Yang Liu,Huanhuan J Wang,Jiangli Zheng,Xin Wang,Han Pan,Ji Li,Junyu Luo,Xuerui Yang,Lester F Lau,H Troy Ghashghaei,Qin Shen

    Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular

  • Osmostress enhances activating phosphorylation of Hog1 MAP kinase by mono-phosphorylated Pbs2 MAP2K.
    EMBO J. (IF 11.227) Pub Date : 2020-02-03
    Kazuo Tatebayashi,Katsuyoshi Yamamoto,Taichiro Tomida,Akiko Nishimura,Tomomi Takayama,Masaaki Oyama,Hiroko Kozuka-Hata,Satomi Adachi-Akahane,Yuji Tokunaga,Haruo Saito

    The MAP kinase (MAPK) Hog1 is the central regulator of osmoadaptation in yeast. When cells are exposed to high osmolarity, the functionally redundant Sho1 and Sln1 osmosensors, respectively, activate the Ste11-Pbs2-Hog1 MAPK cascade and the Ssk2/Ssk22-Pbs2-Hog1 MAPK cascade. In a canonical MAPK cascade, a MAPK kinase kinase (MAP3K) activates a MAPK kinase (MAP2K) by phosphorylating two conserved Ser/Thr

  • Outer membrane lipoprotein NlpI scaffolds peptidoglycan hydrolases within multi-enzyme complexes in Escherichia coli.
    EMBO J. (IF 11.227) Pub Date : 2020-02-03
    Manuel Banzhaf,Hamish Cl Yau,Jolanda Verheul,Adam Lodge,George Kritikos,André Mateus,Baptiste Cordier,Ann Kristin Hov,Frank Stein,Morgane Wartel,Manuel Pazos,Alexandra S Solovyova,Eefjan Breukink,Sven van Teeffelen,Mikhail M Savitski,Tanneke den Blaauwen,Athanasios Typas,Waldemar Vollmer

    The peptidoglycan (PG) sacculus provides bacteria with the mechanical strength to maintain cell shape and resist osmotic stress. Enlargement of the mesh-like sacculus requires the combined activity of peptidoglycan synthases and hydrolases. In Escherichia coli, the activity of two PG synthases is driven by lipoproteins anchored in the outer membrane (OM). However, the regulation of PG hydrolases is

  • α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav 1.2.
    EMBO J. (IF 11.227) Pub Date : 2020-01-27
    Matthew Turner,David E Anderson,Peter Bartels,Madeline Nieves-Cintron,Andrea M Coleman,Peter B Henderson,Kwun Nok Mimi Man,Pang-Yen Tseng,Vladimir Yarov-Yarovoy,Donald M Bers,Manuel F Navedo,Mary C Horne,James B Ames,Johannes W Hell

    The L-type Ca2+ channel CaV 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α-actinin to the IQ motif of CaV 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV 1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646-1,664) bound to α-actinin-1

  • In situ CRISPR-Cas9 base editing for the development of genetically engineered mouse models of breast cancer.
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Stefano Annunziato,Catrin Lutz,Linda Henneman,Jinhyuk Bhin,Kim Wong,Bjørn Siteur,Bas van Gerwen,Renske de Korte-Grimmerink,Maria Paz Zafra,Emma M Schatoff,Anne Paulien Drenth,Eline van der Burg,Timo Eijkman,Siddhartha Mukherjee,Katharina Boroviak,Lodewyk Fa Wessels,Marieke van de Ven,Ivo J Huijbers,David J Adams,Lukas E Dow,Jos Jonkers

    Genetically engineered mouse models (GEMMs) of cancer have proven to be of great value for basic and translational research. Although CRISPR-based gene disruption offers a fast-track approach for perturbing gene function and circumvents certain limitations of standard GEMM development, it does not provide a flexible platform for recapitulating clinically relevant missense mutations in vivo. To this

  • Metabolic switch and epithelial-mesenchymal transition cooperate to regulate pluripotency.
    EMBO J. (IF 11.227) Pub Date : 2020-02-24
    Hao Sun,Xiao Yang,Lining Liang,Mengdan Zhang,Yuan Li,Jinlong Chen,Fuhui Wang,Tingting Yang,Fei Meng,Xiaowei Lai,Changpeng Li,Jingcai He,Meiai He,Qiaoran Xu,Qian Li,Lilong Lin,Duanqing Pei,Hui Zheng

    Both metabolic switch from oxidative phosphorylation to glycolysis (OGS) and epithelial-mesenchymal transition (EMT) promote cellular reprogramming at early stages. However, their connections have not been elucidated. Here, when a chemically defined medium was used to induce early EMT during mouse reprogramming, a facilitated OGS was also observed at the same time. Additional investigations suggested

  • Legionella pneumophila balances ubiquitin transglutamination.
    EMBO J. (IF 11.227) Pub Date : 2020-01-28
    Fujie Yan,Yongqun Zhu,Yan Zhou

    The effector MavC of the bacterial pathogen Legionella pneumophila catalyzes a noncanonical ubiquitination of the host ubiquitin-conjugating E2 enzyme UBE2N by crosslinking a glutamine residue of ubiquitin to UBE2N lysine residues via its transglutaminase activity. A new study by Gan et al (2020) reveals that L. pneumophila reverses this noncanonical ubiquitination via its ubiquitin deamidase effector

  • Legionella pneumophila regulates the activity of UBE2N by deamidase-mediated deubiquitination.
    EMBO J. (IF 11.227) Pub Date : 2019-12-11
    Ninghai Gan,Hongxin Guan,Yini Huang,Ting Yu,Jiaqi Fu,Ernesto S Nakayasu,Kedar Puvar,Chittaranjan Das,Dongmei Wang,Songying Ouyang,Zhao-Qing Luo

    The Legionella pneumophila effector MavC induces ubiquitination of the E2 ubiquitin-conjugating enzyme UBE2N by transglutamination, thereby abolishing its function in the synthesis of K63 -type polyubiquitin chains. The inhibition of UBE2N activity creates a conundrum because this E2 enzyme is important in multiple signaling pathways, including some that are important for intracellular L. pneumophila

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全球疫情及响应:BMC Medicine专题征稿