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  • Munc13 activates the Munc18‐1/syntaxin‐1 complex and enables Munc18‐1 to prime SNARE assembly
    EMBO J. (IF 9.889) Pub Date : 2020-07-09
    Xianping Wang; Jihong Gong; Le Zhu; Shen Wang; Xiaoyu Yang; Yuanyuan Xu; Xiaofei Yang; Cong Ma

    Priming of synaptic vesicles involves Munc13‐catalyzed transition of the Munc18‐1/syntaxin‐1 complex to the SNARE complex in the presence of SNAP ‐25 and synaptobrevin‐2; Munc13 drives opening of syntaxin‐1 via the MUN domain while Munc18‐1 primes SNARE assembly via domain 3a. However, the underlying mechanism remains unclear. In this study, we have identified a number of residues in domain 3a of Munc18‐1

  • Alveolar macrophage‐derived extracellular vesicles inhibit endosomal fusion of influenza virus
    EMBO J. (IF 9.889) Pub Date : 2020-07-09
    Daniel J Schneider; Katherine A Smith; Catrina E Latuszek; Carol A Wilke; Danny M Lyons; Loka R Penke; Jennifer M Speth; Matangi Marthi; Joel A Swanson; Bethany B Moore; Adam S Lauring; Marc Peters‐Golden

    Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza

  • LRRK 2 activation controls the repair of damaged endomembranes in macrophages
    EMBO J. (IF 9.889) Pub Date : 2020-07-09
    Susanne Herbst; Philip Campbell; John Harvey; Elliott M Bernard; Venizelos Papayannopoulos; Nicholas W Wood; Huw R Morris; Maximiliano G Gutierrez

    Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD )‐related kinase LRRK 2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK 2 recruits the

  • Rewired signaling network in T cells expressing the chimeric antigen receptor (CAR )
    EMBO J. (IF 9.889) Pub Date : 2020-07-09
    Rui Dong; Kendra A Libby; Franziska Blaeschke; Walker Fuchs; Alexander Marson; Ronald D Vale; Xiaolei Su

    The chimeric antigen receptor (CAR ) directs T cells to target and kill specific cancer cells. Despite the success of CAR T therapy in clinics, the intracellular signaling pathways that lead to CAR T cell activation remain unclear. Using CD 19 CAR as a model, we report that, similar to the endogenous T cell receptor (TCR ), antigen engagement triggers the formation of CAR microclusters that transduce

  • CCR 5 deficiency/CCR 5Δ32: resistant to HIV infection at the cost of curtailed CD 4+ T cell memory responses
    EMBO J. (IF 9.889) Pub Date : 2020-07-08
    Christoph Matti; Daniel F Legler

    Orchestrated trafficking and activation by pathogen‐derived peptides define the ability of CD 4+ T helper cells to contribute to an effective adaptive immunity. In this issue of The EMBO Journal , Martín‐Leal et al show that the inflammatory chemokine receptor CCR 5, well known for its role in cell migration and HIV infection, regulates ceramide synthesis and TCR nanoclustering to promote memory CD

  • Trnp1 organizes diverse nuclear membrane‐less compartments in neural stem cells
    EMBO J. (IF 9.889) Pub Date : 2020-07-06
    Miriam Esgleas; Sven Falk; Ignasi Forné; Marc Thiry; Sonia Najas; Sirui Zhang; Aina Mas‐Sanchez; Arie Geerlof; Dierk Niessing; Zefeng Wang; Axel Imhof; Magdalena Götz

    TMF1‐regulated nuclear protein 1 (Trnp1) has been shown to exert potent roles in neural development affecting neural stem cell self‐renewal and brain folding, but its molecular function in the nucleus is still unknown. Here, we show that Trnp1 is a low complexity protein with the capacity to phase separate. Trnp1 interacts with factors located in several nuclear membrane‐less organelles, the nucleolus

  • A comparative analysis of the mobility of 45 proteins in the synaptic bouton
    EMBO J. (IF 9.889) Pub Date : 2020-07-06
    Sofiia Reshetniak; Jan‐Eike Ußling; Eleonora Perego; Burkhard Rammner; Thomas Schikorski; Eugenio F Fornasiero; Sven Truckenbrodt; Sarah Köster; Silvio O Rizzoli

    Many proteins involved in synaptic transmission are well known, and their features, as their abundance or spatial distribution, have been analyzed in systematic studies. This has not been the case, however, for their mobility. To solve this, we analyzed the motion of 45 GFP‐tagged synaptic proteins expressed in cultured hippocampal neurons, using fluorescence recovery after photobleaching, particle

  • Transient exposure to miR‐203 enhances the differentiation capacity of established pluripotent stem cells
    EMBO J. (IF 9.889) Pub Date : 2020-07-02
    María Salazar‐Roa; Marianna Trakala; Mónica Álvarez‐Fernández; Fátima Valdés‐Mora; Cuiqing Zhong; Jaime Muñoz; Yang Yu; Timothy J Peters; Osvaldo Graña‐Castro; Rosa Serrano; Elisabet Zapatero‐Solana; María Abad; María José Bueno; Marta Gómez de Cedrón; José Fernández‐Piqueras; Manuel Serrano; María A Blasco; Da‐Zhi Wang; Susan J Clark; Juan Carlos Izpisua‐Belmonte; Sagrario Ortega; Marcos Malumbres

    Full differentiation potential along with self‐renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro . We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already‐established murine and human

  • SUMOylated PRC1 controls histone H3.3 deposition and genome integrity of embryonic heterochromatin.
    EMBO J. (IF 9.889) Pub Date : 2020-05-12
    Zichuan Liu,Mathieu Tardat,Mark E Gill,Helene Royo,Raphael Thierry,Evgeniy A Ozonov,Antoine Hfm Peters

    Chromatin integrity is essential for cellular homeostasis. Polycomb group proteins modulate chromatin states and transcriptionally repress developmental genes to maintain cell identity. They also repress repetitive sequences such as major satellites and constitute an alternative state of pericentromeric constitutive heterochromatin at paternal chromosomes (pat‐PCH ) in mouse pre‐implantation embryos

  • Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage.
    EMBO J. (IF 9.889) Pub Date : 2020-06-02
    Joffrey Pelletier,Ferran Riaño-Canalias,Eugènia Almacellas,Caroline Mauvezin,Sara Samino,Sonia Feu,Sandra Menoyo,Ana Domostegui,Marta Garcia-Cajide,Ramon Salazar,Constanza Cortés,Ricard Marcos,Albert Tauler,Oscar Yanes,Neus Agell,Sara C Kozma,Antonio Gentilella,George Thomas

    Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC ) and the DNA damage response (DDR ) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC

  • The chromatin remodeler SRCAP promotes self-renewal of intestinal stem cells.
    EMBO J. (IF 9.889) Pub Date : 2020-05-25
    Buqing Ye,Liuliu Yang,Guomin Qian,Benyu Liu,Xiaoxiao Zhu,Pingping Zhu,Jing Ma,Wei Xie,Huimu Li,Tianku Lu,Yanying Wang,Shuo Wang,Ying Du,Zhimin Wang,Jing Jiang,Jinsong Li,Dongdong Fan,Shu Meng,Jiayi Wu,Yong Tian,Zusen Fan

    Lgr5+ intestinal stem cells (ISC s) exhibit self‐renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self‐renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISC s. Srcap deletion impairs both self‐renewal of ISC s and intestinal epithelial regeneration. Mechanistically

  • The cold response regulator CBF1 promotes Arabidopsis hypocotyl growth at ambient temperatures.
    EMBO J. (IF 9.889) Pub Date : 2020-05-25
    Xiaojing Dong,Yan Yan,Bochen Jiang,Yiting Shi,Yuxin Jia,Jinkui Cheng,Yihao Shi,Juqing Kang,Hong Li,Dun Zhang,Lijuan Qi,Run Han,Shaoman Zhang,Yangyang Zhou,Xiaoji Wang,William Terzaghi,Hongya Gu,Dingming Kang,Shuhua Yang,Jigang Li

    Light and temperature are two core environmental factors that coordinately regulate plant growth and survival throughout their entire life cycle. However, the mechanisms integrating light and temperature signaling pathways in plants remain poorly understood. Here, we report that CBF 1, an AP 2/ERF ‐family transcription factor essential for plant cold acclimation, promotes hypocotyl growth under ambient

  • Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope functions.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Miriam Kutsch,Linda Sistemich,Cammie F Lesser,Marcia B Goldberg,Christian Herrmann,Jörn Coers

    In the outer membrane of gram‐negative bacteria, O‐antigen segments of lipopolysaccharide (LPS) form a chemomechanical barrier, whereas lipid A moieties anchor LPS molecules. Upon infection, human guanylate binding protein‐1 (hGBP1) colocalizes with intracellular gram‐negative bacterial pathogens, facilitates bacterial killing, promotes activation of the lipid A sensor caspase‐4, and blocks actin‐driven

  • A protein palmitoylation cascade regulates microtubule cytoskeleton integrity in Plasmodium.
    EMBO J. (IF 9.889) Pub Date : 2020-05-12
    Xu Wang,Pengge Qian,Huiting Cui,Luming Yao,Jing Yuan

    Morphogenesis of many protozoans depends on a polarized establishment of cytoskeletal structures. In malaria‐causing parasites, this can be observed when a round zygote develops into an elongated motile ookinete within the mosquito stomach. This morphogenesis is mediated by the pellicle cytoskeletal structures, including the inner membrane complex (IMC) and the underlying subpellicular microtubules

  • The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species.
    EMBO J. (IF 9.889) Pub Date : 2020-05-25
    Jessica Tittelmeier,Carl Alexander Sandhof,Heidrun Maja Ries,Silke Druffel-Augustin,Axel Mogk,Bernd Bukau,Carmen Nussbaum-Krammer

    The accumulation and prion‐like propagation of α‐synuclein and other amyloidogenic proteins are associated with devastating neurodegenerative diseases. Metazoan heat shock protein HSP70 and its co‐chaperones DNAJB1 and HSP110 constitute a disaggregation machinery that is able to disassemble α‐synuclein fibrils in vitro , but its physiological effects on α‐synuclein toxicity are unknown. Here, we depleted

  • NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients.
    EMBO J. (IF 9.889) Pub Date : 2020-06-02
    Michele Bertacchi,Anna Lisa Romano,Agnès Loubat,Frederic Tran Mau-Them,Marjolaine Willems,Laurence Faivre,Philippe Khau van Kien,Laurence Perrin,Françoise Devillard,Arthur Sorlin,Paul Kuentz,Christophe Philippe,Aurore Garde,Francesco Neri,Rossella Di Giaimo,Salvatore Oliviero,Silvia Cappello,Ludovico D'Incerti,Carolina Frassoni,Michèle Studer

    The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra‐Bosch‐Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss‐of‐function

  • Myeloid cells protect intestinal epithelial barrier integrity through the angiogenin/plexin-B2 axis.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Rongpan Bai,Desen Sun,Muxiong Chen,Xiaoliang Shi,Liang Luo,Zhengrong Yao,Yaxin Liu,Xiaolong Ge,Xiangwei Gao,Guo-Fu Hu,Wei Zhou,Jinghao Sheng,Zhengping Xu

    Communication between myeloid cells and epithelium plays critical role in maintaining intestinal epithelial barrier integrity. Myeloid cells interact with intestinal epithelial cells (IEC s) by producing various mediators; however, the molecules mediating their crosstalk remain incompletely understood. Here, we report that deficiency of angiogenin (Ang ) in mouse myeloid cells caused impairment of

  • Structural basis of semaphorin-plexin cis interaction.
    EMBO J. (IF 9.889) Pub Date : 2020-06-05
    Daniel Rozbesky,Marieke G Verhagen,Dimple Karia,Gergely N Nagy,Luis Alvarez,Ross A Robinson,Karl Harlos,Sergi Padilla-Parra,R Jeroen Pasterkamp,Edith Yvonne Jones

    Semaphorin ligands interact with plexin receptors to contribute to functions in the development of myriad tissues including neurite guidance and synaptic organisation within the nervous system. Cell‐attached semaphorins interact in trans with plexins on opposing cells, but also in cis on the same cell. The interplay between trans and cis interactions is crucial for the regulated development of complex

  • Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits.
    EMBO J. (IF 9.889) Pub Date : 2020-05-13
    Thomas Kruse,Sebastian Peter Gnosa,Isha Nasa,Dimitriya Hristoforova Garvanska,Jamin B Hein,Hieu Nguyen,Jacob Samsøe-Petersen,Blanca Lopez-Mendez,Emil Peter Thrane Hertz,Jeanette Schwarz,Hanna Sofia Pena,Denise Nikodemus,Marie Kveiborg,Arminja N Kettenbach,Jakob Nilsson

    PP2A is an essential protein phosphatase that regulates most cellular processes through the formation of holoenzymes containing distinct regulatory B‐subunits. Only a limited number of PP2A‐regulated phosphorylation sites are known. This hampers our understanding of the mechanisms of site‐specific dephosphorylation and of its tumor suppressor functions. Here, we develop phosphoproteomic strategies

  • Deciphering the regulatory landscape of fetal and adult γδ T‐cell development at single‐cell resolution
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
      Sagar; Maria Pokrovskii; Josip S Herman; Shruti Naik; Elisabeth Sock; Patrice Zeis; Ute Lausch; Michael Wegner; Yakup Tanriver; Dan R Littman; Dominic Grün

    γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high‐resolution map of γδ T‐cell differentiation

  • A novel approach to measure mitochondrial respiration in frozen biological samples.
    EMBO J. (IF 9.889) Pub Date : 2020-05-20
    Rebeca Acin-Perez,Ilan Y Benador,Anton Petcherski,Michaela Veliova,Gloria A Benavides,Sylviane Lagarrigue,Arianne Caudal,Laurent Vergnes,Anne N Murphy,Georgios Karamanlidis,Rong Tian,Karen Reue,Jonathan Wanagat,Harold Sacks,Francesca Amati,Victor M Darley-Usmar,Marc Liesa,Ajit S Divakaruni,Linsey Stiles,Orian S Shirihai

    Respirometry is the gold standard measurement of mitochondrial oxidative function, as it reflects the activity of the electron transport chain complexes working together. However, the requirement for freshly isolated mitochondria hinders the feasibility of respirometry in multi‐site clinical studies and retrospective studies. Here, we describe a novel respirometry approach suited for frozen samples

  • Structural insights into mammalian mitochondrial translation elongation catalyzed by mtEFG 1
    EMBO J. (IF 9.889) Pub Date : 2020-06-30
    Eva Kummer; Nenad Ban

    Mitochondria are eukaryotic organelles of bacterial origin where respiration takes place to produce cellular chemical energy. These reactions are catalyzed by the respiratory chain complexes located in the inner mitochondrial membrane. Notably, key components of the respiratory chain complexes are encoded on the mitochondrial chromosome and their expression relies on a dedicated mitochondrial translation

  • Identification and characterization of diverse OTU deubiquitinases in bacteria.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Alexander F Schubert,Justine V Nguyen,Tyler G Franklin,Paul P Geurink,Cameron G Roberts,Daniel J Sanderson,Lauren N Miller,Huib Ovaa,Kay Hofmann,Jonathan N Pruneda,David Komander

    Manipulation of host ubiquitin signaling is becoming an increasingly apparent evolutionary strategy among bacterial and viral pathogens. By removing host ubiquitin signals, for example, invading pathogens can inactivate immune response pathways and evade detection. The ovarian tumor (OTU) family of deubiquitinases regulates diverse ubiquitin signals in humans. Viral pathogens have also extensively

  • MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Till Stephan,Christian Brüser,Markus Deckers,Anna M Steyer,Francisco Balzarotti,Mariam Barbot,Tiana S Behr,Gudrun Heim,Wolfgang Hübner,Peter Ilgen,Felix Lange,David Pacheu-Grau,Jasmin K Pape,Stefan Stoldt,Thomas Huser,Stefan W Hell,Wiebke Möbius,Peter Rehling,Dietmar Riedel,Stefan Jakobs

    Mitochondrial function is critically dependent on the folding of the mitochondrial inner membrane into cristae; indeed, numerous human diseases are associated with aberrant crista morphologies. With the MICOS complex, OPA1 and the F1Fo‐ATP synthase, key players of cristae biogenesis have been identified, yet their interplay is poorly understood. Harnessing super‐resolution light and 3D electron microscopy

  • Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Martina Pigoni,Hung-En Hsia,Jana Hartmann,Jasenka Rudan Njavro,Merav D Shmueli,Stephan A Müller,Gökhan Güner,Johanna Tüshaus,Peer-Hendrik Kuhn,Rohit Kumar,Pan Gao,Mai Ly Tran,Bulat Ramazanov,Birgit Blank,Agnes L Hipgrave Ederveen,Julia Von Blume,Christophe Mulle,Jenny M Gunnersen,Manfred Wuhrer,Gerhard Rammes,Marc Aurel Busche,Thomas Koeglsperger,Stefan F Lichtenthaler

    Seizure protein 6 (SEZ6) is required for the development and maintenance of the nervous system, is a major substrate of the protease BACE1 and is linked to Alzheimer's disease (AD) and psychiatric disorders, but its molecular functions are not well understood. Here, we demonstrate that SEZ6 controls glycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits. Loss

  • Resolving mitochondrial cristae: introducing a new model into the fold.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Kate McArthur,Michael T Ryan

    The many functions of mitochondria—the powerhouses of our cells—are intimately linked with their ultrastructure and network morphology. In this issue, Stephan et al (2020) apply a tour de force of microscopic techniques to examine the contributions of specific mitochondrial proteins to crista architecture.

  • Structural insights into actin filament recognition by commonly used cellular actin markers.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Archana Kumari,Shubham Kesarwani,Manjunath G Javoor,Kutti R Vinothkumar,Minhajuddin Sirajuddin

    Cellular studies of filamentous actin (F‐actin) processes commonly utilize fluorescent versions of toxins, peptides, and proteins that bind actin. While the choice of these markers has been largely based on availability and ease, there is a severe dearth of structural data for an informed judgment in employing suitable F‐actin markers for a particular requirement. Here, we describe the electron cryomicroscopy

  • Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.
    EMBO J. (IF 9.889) Pub Date : 2020-06-22
    Anaelle A Dumas,Nicola Pomella,Gabriel Rosser,Loredana Guglielmi,Claire Vinel,Thomas O Millner,Jeremy Rees,Natasha Aley,Denise Sheer,Jun Wei,Anantha Marisetty,Amy B Heimberger,Robert L Bowman,Sebastian Brandner,Johanna A Joyce,Silvia Marino

    Tumour‐associated microglia/macrophages (TAM ) are the most numerous non‐neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM ), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM , but little is known about the potential role of this pathway in TAM . Here, we show that

  • Plant E3 ligases SNIPER1 and SNIPER2 broadly regulate the homeostasis of sensor NLR immune receptors.
    EMBO J. (IF 9.889) Pub Date : 2020-06-18
    Zhongshou Wu,Meixuezi Tong,Lei Tian,Chipan Zhu,Xueru Liu,Yuelin Zhang,Xin Li

    In both plants and animals, nucleotide‐binding leucine‐rich repeat (NLR ) immune receptors perceive pathogen‐derived molecules to trigger immunity. Global NLR homeostasis must be tightly controlled to ensure sufficient and timely immune output while avoiding aberrant activation, the mechanisms of which are largely unclear. In a previous reverse genetic screen, we identified two novel E3 ligases, SNIPER

  • Hsp42 is the general small heat shock protein in the cytosol of Saccharomyces cerevisiae.
    EMBO J. (IF 9.889) Pub Date : 2020-06-17
    Martin Haslbeck,Nathalie Braun,Thusnelda Stromer,Bettina Richter,Natascha Model,Sevil Weinkauf,Johannes Buchner

  • CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy.
    EMBO J. (IF 9.889) Pub Date : 2020-06-11
    Thaddaeus Mutugi Nthiga,Birendra Kumar Shrestha,Eva Sjøttem,Jack-Ansgar Bruun,Kenneth Bowitz Larsen,Zambarlal Bhujabal,Trond Lamark,Terje Johansen

    The endoplasmic reticulum (ER ) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER ‐phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER ‐resident proteins have been identified as ER

  • CCR5 deficiency impairs CD4+ T-cell memory responses and antigenic sensitivity through increased ceramide synthesis.
    EMBO J. (IF 9.889) Pub Date : 2020-06-11
    Ana Martín-Leal,Raquel Blanco,Josefina Casas,María E Sáez,Elena Rodríguez-Bovolenta,Itziar de Rojas,Carina Drechsler,Luis Miguel Real,Gemma Fabrias,Agustín Ruíz,Mario Castro,Wolfgang Wa Schamel,Balbino Alarcón,Hisse M van Santen,Santos Mañes

    CCR 5 is not only a coreceptor for HIV ‐1 infection in CD 4+ T cells, but also contributes to their functional fitness. Here, we show that by limiting transcription of specific ceramide synthases, CCR 5 signaling reduces ceramide levels and thereby increases T‐cell antigen receptor (TCR ) nanoclustering in antigen‐experienced mouse and human CD 4+ T cells. This activity is CCR 5‐specific and independent

  • Auto-inhibition of Mif2/CENP-C ensures centromere-dependent kinetochore assembly in budding yeast.
    EMBO J. (IF 9.889) Pub Date : 2020-06-09
    Kerstin Killinger,Miriam Böhm,Philine Steinbach,Götz Hagemann,Mike Blüggel,Karolin Jänen,Simone Hohoff,Peter Bayer,Franz Herzog,Stefan Westermann

    Kinetochores are chromatin‐bound multi‐protein complexes that allow high‐fidelity chromosome segregation during mitosis and meiosis. Kinetochore assembly is exclusively initiated at chromatin containing Cse4/CENP‐A nucleosomes. The molecular mechanisms ensuring that subcomplexes assemble efficiently into kinetochores only at centromeres, but not anywhere else, are incompletely understood. Here, we

  • SAMHD1-mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Afzal Husain,Jiangliang Xu,Hodaka Fujii,Mikiyo Nakata,Maki Kobayashi,Ji-Yang Wang,Jan Rehwinkel,Tasuku Honjo,Nasim A Begum

    Sterile alpha motif and histidine‐aspartic acid domain‐containing protein 1 (SAMHD 1), a dNTP triphosphohydrolase, regulates the levels of cellular dNTP s through their hydrolysis. SAMHD 1 protects cells from invading viruses that depend on dNTP s to replicate and is frequently mutated in cancers and Aicardi–Goutières syndrome, a hereditary autoimmune encephalopathy. We discovered that SAMHD 1 localizes

  • MDMX inhibits casein kinase 1α activity and stimulates Wnt signaling.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Qingling Huang,Lihong Chen,Ernst Schonbrunn,Jiandong Chen

    Casein kinase 1 alpha (CK 1α) is a serine/threonine kinase with numerous functions, including regulating the Wnt/β‐catenin and p53 pathways. CK 1α has a well‐established role in inhibiting the p53 tumor suppressor by binding to MDMX and stimulating MDMX ‐p53 interaction. MDMX purified from cells contains near‐stoichiometric amounts of CK 1α, suggesting that MDMX may in turn regulate CK 1α function

  • NAADP-regulated two-pore channels drive phagocytosis through endo-lysosomal Ca2+ nanodomains, calcineurin and dynamin.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Lianne C Davis,Anthony J Morgan,Antony Galione

    Macrophages clear pathogens by phagocytosis and lysosomes that fuse with phagosomes are traditionally regarded as to a source of membranes and luminal degradative enzymes. Here, we reveal that endo‐lysosomes act as platforms for a new phagocytic signalling pathway in which FcγR activation recruits the second messenger NAADP and thereby promotes the opening of Ca2+‐permeable two‐pore channels (TPC s)

  • Multiple pathways coordinate assembly of human mitochondrial complex IV and stabilization of respiratory supercomplexes.
    EMBO J. (IF 9.889) Pub Date : 2020-06-08
    Teresa Lobo-Jarne,Rafael Pérez-Pérez,Flavia Fontanesi,Alba Timón-Gómez,Ilka Wittig,Ana Peñas,Pablo Serrano-Lorenzo,Inés García-Consuegra,Joaquín Arenas,Miguel A Martín,Antoni Barrientos,Cristina Ugalde

    Mitochondrial respiratory chain complexes I, III, and IV can associate into larger structures termed supercomplexes or respirasomes, thereby generating structural interdependences among the individual complexes yet to be understood. In patients, nonsense mutations in complex IV subunit genes cause severe encephalomyopathies randomly associated with pleiotropic complex I defects. Using complexome profiling

  • Highly active rubiscos discovered by systematic interrogation of natural sequence diversity.
    EMBO J. (IF 9.889) Pub Date : 2020-06-05
    Dan Davidi,Melina Shamshoum,Zhijun Guo,Yinon M Bar-On,Noam Prywes,Aia Oz,Jagoda Jablonska,Avi Flamholz,David G Wernick,Niv Antonovsky,Benoit de Pins,Lior Shachar,Dina Hochhauser,Yoav Peleg,Shira Albeck,Itai Sharon,Oliver Mueller-Cajar,Ron Milo

    CO 2 is converted into biomass almost solely by the enzyme rubisco. The poor carboxylation properties of plant rubiscos have led to efforts that made it the most kinetically characterized enzyme, yet these studies focused on < 5% of its natural diversity. Here, we searched for fast‐carboxylating variants by systematically mining genomic and metagenomic data. Approximately 33,000 unique rubisco sequences

  • Dysfunctional oxidative phosphorylation shunts branched-chain amino acid catabolism onto lipogenesis in skeletal muscle.
    EMBO J. (IF 9.889) Pub Date : 2020-06-03
    Cristina Sánchez-González,Cristina Nuevo-Tapioles,Juan Cruz Herrero Martín,Marta P Pereira,Sandra Serrano Sanz,Ana Ramírez de Molina,José M Cuezva,Laura Formentini

    It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole‐body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl‐glycerides, and higher visceral adipose

  • Feedback regulation of heat shock factor 1 (Hsf1) activity by Hsp70-mediated trimer unzipping and dissociation from DNA.
    EMBO J. (IF 9.889) Pub Date : 2020-06-03
    Szymon W Kmiecik,Laura Le Breton,Matthias P Mayer

    The heat shock response is a universal transcriptional response to proteotoxic stress orchestrated by heat shock transcription factor Hsf1 in all eukaryotic cells. Despite over 40 years of intense research, the mechanism of Hsf1 activity regulation remains poorly understood at the molecular level. In metazoa, Hsf1 trimerizes upon heat shock through a leucine‐zipper domain and binds to DNA . How Hsf1

  • Structural basis of bacterial σ28 -mediated transcription reveals roles of the RNA polymerase zinc-binding domain.
    EMBO J. (IF 9.889) Pub Date : 2020-06-02
    Wei Shi,Wei Zhou,Baoyue Zhang,Shaojia Huang,Yanan Jiang,Abigail Schammel,Yangbo Hu,Bin Liu

    In bacteria, σ28 is the flagella‐specific sigma factor that targets RNA polymerase (RNAP ) to control the expression of flagella‐related genes involving bacterial motility and chemotaxis. However, the structural mechanism of σ28‐dependent promoter recognition remains uncharacterized. Here, we report cryo‐EM structures of E. coli σ28‐dependent transcribing complexes on a complete flagella‐specific promoter

  • Tissue-resident macrophages actively suppress IL-1beta release via a reactive prostanoid/IL-10 pathway.
    EMBO J. (IF 9.889) Pub Date : 2020-06-02
    Natacha Ipseiz,Robert J Pickering,Marcela Rosas,Victoria J Tyrrell,Luke C Davies,Selinda J Orr,Magdalena A Czubala,Dina Fathalla,Avril Ab Robertson,Clare E Bryant,Valerie O'Donnell,Philip R Taylor

    The alarm cytokine interleukin‐1β (IL‐1β) is a potent activator of the inflammatory cascade following pathogen recognition. IL‐1β production typically requires two signals: first, priming by recognition of pathogen‐associated molecular patterns leads to the production of immature pro‐IL‐1β; subsequently, inflammasome activation by a secondary signal allows cleavage and maturation of IL‐1β from its

  • ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways.
    EMBO J. (IF 9.889) Pub Date : 2020-06-02
    Xu Feng,Anthony Tubbs,Chunchao Zhang,Mengfan Tang,Sriram Sridharan,Chao Wang,Dadi Jiang,Dan Su,Huimin Zhang,Zhen Chen,Litong Nie,Yun Xiong,Min Huang,André Nussenzweig,Junjie Chen

    Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation‐induced innate immune responses. Using a series of mammalian knockout cell lines, we

  • A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding.
    EMBO J. (IF 9.889) Pub Date : 2020-05-25
    Tao Li,Brian Chiou,Casey K Gilman,Rong Luo,Tatsuhiro Koshi,Diankun Yu,Hayeon C Oak,Stefanie Giera,Erin Johnson-Venkatesh,Allie K Muthukumar,Beth Stevens,Hisashi Umemori,Xianhua Piao

    Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein‐coupled receptor ADGRG 1/GPR 56 controls multiple

  • Spindle checkpoint: trapped by the corona, cyclin B1 goes MAD.
    EMBO J. (IF 9.889) Pub Date : 2020-05-18
    Carlos Conde,Reto Gassmann

    The spindle checkpoint protects against aneuploidy by ensuring that dividing cells only proceed with chromosome segregation once all kinetochores are stably attached to spindle microtubules. The checkpoint protein MAD 1 localizes to the corona, a structural expansion of the kinetochore forming in the absence of microtubule attachment, but molecular mechanism or functional significance of this localization

  • Dynamic properties of noise and Her6 levels are optimized by miR-9, allowing the decoding of the Her6 oscillator.
    EMBO J. (IF 9.889) Pub Date : 2020-05-12
    Ximena Soto,Veronica Biga,Jochen Kursawe,Robert Lea,Parnian Doostdar,Riba Thomas,Nancy Papalopulu

    Noise is prevalent in biology and has been widely quantified using snapshot measurements. This static view obscures our understanding of dynamic noise properties and how these affect gene expression and cell state transitions. Using a CRISPR /Cas9 Zebrafish her6::Venus reporter combined with mathematical and in vivo experimentation, we explore how noise affects the protein dynamics of Her6, a basic

  • Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity.
    EMBO J. (IF 9.889) Pub Date : 2020-05-07
    Hirotaka Kanoh,Takahiro Nitta,Shinji Go,Kei-Ichiro Inamori,Lucas Veillon,Wataru Nihei,Mayu Fujii,Kazuya Kabayama,Atsushi Shimoyama,Koichi Fukase,Umeharu Ohto,Toshiyuki Shimizu,Taku Watanabe,Hiroki Shindo,Sorama Aoki,Kenichi Sato,Mika Nagasaki,Yutaka Yatomi,Naoko Komura,Hiromune Ando,Hideharu Ishida,Makoto Kiso,Yoshihiro Natori,Yuichi Yoshimura,Asia Zonca,Anna Cattaneo,Marilena Letizia,Maria Ciampa

    Innate immune signaling via TLR 4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear. GM 3 ganglioside in human serum is composed of a variety of fatty acids, including long‐chain (LCFA ) and very‐long‐chain (VLCFA ). Analysis of circulating levels of human serum GM 3 species from

  • Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome.
    EMBO J. (IF 9.889) Pub Date : 2020-05-05
    Tatsuo Miyamoto,Kosuke Hosoba,Takeshi Itabashi,Atsuko H Iwane,Silvia Natsuko Akutsu,Hiroshi Ochiai,Yumiko Saito,Takashi Yamamoto,Shinya Matsuura

    Primary cilia are antenna‐like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven‐transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is

  • RNA m6 A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.
    EMBO J. (IF 9.889) Pub Date : 2020-05-05
    Ziyou Lin,Yi Niu,Arabella Wan,Dongshi Chen,Heng Liang,Xijun Chen,Lei Sun,Siyue Zhan,Liutao Chen,Chao Cheng,Xiaolei Zhang,Xianzhang Bu,Weiling He,Guohui Wan

    N6‐methyladenosine (m6A) is an abundant nucleotide modification in mRNA , known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL 3, a primary m6A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma

  • One too many: the surprising heterogeneity of Drosophila macrophages.
    EMBO J. (IF 9.889) Pub Date : 2020-05-04
    Volker Hartenstein

    Macrophages are motile cells that roam the extracellular spaces within organs or the body cavity and carry out essential functions in organ development and immunity. New work published in The EMBO Journal adds surprising new insights into the heterogeneity of Drosophila macrophages revealing many similarities to their vertebrate counterparts.

  • Cyclin A triggers Mitosis either via the Greatwall kinase pathway or Cyclin B.
    EMBO J. (IF 9.889) Pub Date : 2020-04-30
    Nadia Hégarat,Adrijana Crncec,Maria F Suarez Peredo Rodriguez,Fabio Echegaray Iturra,Yan Gu,Oliver Busby,Paul F Lang,Alexis R Barr,Chris Bakal,Masato T Kanemaki,Angus I Lamond,Bela Novak,Tony Ly,Helfrid Hochegger

    Two mitotic cyclin types, cyclin A and B, exist in higher eukaryotes, but their specialised functions in mitosis are incompletely understood. Using degron tags for rapid inducible protein removal, we analyse how acute depletion of these proteins affects mitosis. Loss of cyclin A in G2‐phase prevents mitotic entry. Cells lacking cyclin B can enter mitosis and phosphorylate most mitotic proteins, because

  • Behind closed gates - chaperones and charged residues determine protein fate.
    EMBO J. (IF 9.889) Pub Date : 2020-04-30
    Margreet B Koopman,Stefan Gd Rüdiger

    Charged residues flanking aggregation‐prone regions play a role in protein folding and prevention of aggregation. In this issue of The EMBO Journal , Houben et al exploit the role of such charged gatekeepers in aggregation suppression and find that negative charges are more effective than positive ones. Strikingly, the prominent Hsp70 chaperone has a strong preference for the less effective, basic

  • Structural basis for loading and inhibition of a bacterial T6SS phospholipase effector by the VgrG spike.
    EMBO J. (IF 9.889) Pub Date : 2020-04-30
    Nicolas Flaugnatti,Chiara Rapisarda,Martial Rey,Solène G Beauvois,Viet Anh Nguyen,Stéphane Canaan,Eric Durand,Julia Chamot-Rooke,Eric Cascales,Rémi Fronzes,Laure Journet

    The bacterial type VI secretion system (T6SS) is a macromolecular machine that injects effectors into prokaryotic and eukaryotic cells. The mode of action of the T6SS is similar to contractile phages: the contraction of a sheath structure pushes a tube topped by a spike into target cells. Effectors are loaded onto the spike or confined into the tube. In enteroaggregative Escherichia coli , the Tle1

  • RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.
    EMBO J. (IF 9.889) Pub Date : 2020-04-29
    Yoko Fukushima,Koichi Nishiyama,Hiroshi Kataoka,Marcus Fruttiger,Shigetomo Fukuhara,Kohji Nishida,Naoki Mochizuki,Hiroki Kurihara,Shin-Ichi Nishikawa,Akiyoshi Uemura

    During angiogenesis, VEGF acts as an attractive cue for endothelial cells (EC s), while Sema3E mediates repulsive cues. Here, we show that the small GTP ase RhoJ integrates these opposing signals in directional EC migration. In the GTP ‐bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1‐bound RhoJ

  • Splice-dependent trans-synaptic PTPδ-IL1RAPL1 interaction regulates synapse formation and non-REM sleep.
    EMBO J. (IF 9.889) Pub Date : 2020-04-29
    Haram Park,Yeonsoo Choi,Hwajin Jung,Seoyeong Kim,Suho Lee,Hyemin Han,Hanseul Kweon,Suwon Kang,Woong Seob Sim,Frank Koopmans,Esther Yang,Hyun Kim,August B Smit,Yong Chul Bae,Eunjoon Kim

    Alternative splicing regulates trans‐synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTP δ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTP δ is mainly present at excitatory presynaptic sites by endogenous

  • BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.
    EMBO J. (IF 9.889) Pub Date : 2020-04-29
    Zhaohua Hu,Shaojie Mi,Ting Zhao,Changmin Peng,Yihan Peng,Lulu Chen,Wenge Zhu,Yi Yao,Qibin Song,Xiangpan Li,Xinzhi Li,Chenxi Jia,Huadong Pei

    Long non‐coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP‐qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous

  • Bacterial rhomboid proteases mediate quality control of orphan membrane proteins.
    EMBO J. (IF 9.889) Pub Date : 2020-04-27
    Guangyu Liu,Stephen E Beaton,Adam G Grieve,Rhiannon Evans,Miranda Rogers,Kvido Strisovsky,Fraser A Armstrong,Matthew Freeman,Rachel M Exley,Christoph M Tang

    Although multiprotein membrane complexes play crucial roles in bacterial physiology and virulence, the mechanisms governing their quality control remain incompletely understood. In particular, it is not known how unincorporated, orphan components of protein complexes are recognised and eliminated from membranes. Rhomboids, the most widespread and largest superfamily of intramembrane proteases, are

  • Optimal sidestepping of intraflagellar transport kinesins regulates structure and function of sensory cilia.
    EMBO J. (IF 9.889) Pub Date : 2020-04-27
    Chao Xie,Liuju Li,Ming Li,Wenxin Shao,Qingyu Zuo,Xiaoshuai Huang,Riwang Chen,Wei Li,Melanie Brunnbauer,Zeynep Ökten,Liangyi Chen,Guangshuo Ou

    Cytoskeletal‐based molecular motors produce force perpendicular to their direction of movement. However, it remains unknown whether and why motor proteins generate sidesteps movement along their filamentous tracks in vivo . Using Hessian structured illumination microscopy, we located green fluorescent protein (GFP)‐labeled intraflagellar transport (IFT) particles inside sensory cilia of live Caenorhabditis

  • Derlins with scissors: primordial ERAD in bacteria.
    EMBO J. (IF 9.889) Pub Date : 2020-04-27
    Julia D Knopf,Marius K Lemberg

    Rhomboid intramembrane serine proteases are present in all kingdoms of life, but as we do not know their substrates in many species, it remains puzzling why rhomboids are among the most-conserved integral membrane proteins. Two new studies in The EMBO Journal by Began et al and Liu et al now link bacterial rhomboid proteases to membrane protein degradation, showing striking similarities to what is

  • Compromised DNA repair is responsible for diabetes-associated fibrosis.
    EMBO J. (IF 9.889) Pub Date : 2020-04-27
    Varun Kumar,Raman Agrawal,Aparamita Pandey,Stefan Kopf,Manuel Hoeffgen,Serap Kaymak,Obul Reddy Bandapalli,Vera Gorbunova,Andrei Seluanov,Marcus A Mall,Stephan Herzig,Peter P Nawroth

    Diabetes‐associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and

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