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  •   Nascent polypeptide within the exit tunnel stabilizes the ribosome to counteract risky translation
    EMBO J. (IF 11.598) Pub Date : 2021-10-20
    Yuhei Chadani, Nobuyuki Sugata, Tatsuya Niwa, Yosuke Ito, Shintaro Iwasaki, Hideki Taguchi

    Continuous translation elongation, irrespective of amino acid sequences, is a prerequisite for living organisms to produce their proteomes. However, nascent polypeptide products bear an inherent risk of elongation abortion. For example, negatively charged sequences with occasional intermittent prolines, termed intrinsic ribosome destabilization (IRD) sequences, weaken the translating ribosomal complex

  •   Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane
    EMBO J. (IF 11.598) Pub Date : 2021-10-18
    Yang Xu, Hediye Erdjument-Bromage, Colin K L Phoon, Thomas A Neubert, Mindong Ren, Michael Schlame

    Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the

  •   Seeing eye to eye: photoreceptors employ nanotube-like connections for material transfer
    EMBO J. (IF 11.598) Pub Date : 2021-10-18
    J Michael Henderson, Chiara Zurzolo

    Cytoskeletal protrusions are emerging as key elements in the development of cellular networks through which material is readily exchanged. In parallel studies, Ortin-Martinez et al (2021) and Kalargyrou et al (2021) report for the first time a direct transfer of cytoplasmic and membrane-bound material between photoreceptors through nanotube-like connections, providing further evidence toward the existence

  •   Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration
    EMBO J. (IF 11.598) Pub Date : 2021-10-18
    Sunanjay Bajaj, Joshua A Bagley, Christoph Sommer, Abel Vertesy, Sakurako Nagumo Wong, Veronica Krenn, Julie Lévi-Strauss, Juergen A Knoblich

    Inhibitory GABAergic interneurons migrate over long distances from their extracortical origin into the developing cortex. In humans, this process is uniquely slow and prolonged, and it is unclear whether guidance cues unique to humans govern the various phases of this complex developmental process. Here, we use fused cerebral organoids to identify key roles of neurotransmitter signaling pathways in

  •   The Hda1 histone deacetylase limits divergent non-coding transcription and restricts transcription initiation frequency
    EMBO J. (IF 11.598) Pub Date : 2021-10-18
    Uthra Gowthaman, Maxim Ivanov, Isabel Schwarz, Heta P Patel, Niels A Müller, Desiré García-Pichardo, Tineke L Lenstra, Sebastian Marquardt

    Nucleosome-depleted regions (NDRs) at gene promoters support initiation of RNA polymerase II transcription. Interestingly, transcription often initiates in both directions, resulting in an mRNA and a divergent non-coding (DNC) transcript of unclear purpose. Here, we characterized the genetic architecture and molecular mechanism of DNC transcription in budding yeast. Using high-throughput reverse genetic

  •   A killer metamorphosis: catching BAK in action at the membrane
    EMBO J. (IF 11.598) Pub Date : 2021-09-20
    Adedolapo M Ojoawo, Tudor Moldoveanu

    Permeabilization of the outer mitochondrial membrane initiates apoptotic cell death. B-cell lymphoma 2 (BCL-2) antagonist killer (BAK) and BCL-2-associated X (BAX) mediate mitochondrial poration, but how this process unfolds remains poorly defined. Two studies in this issue investigate the transition of dormant, inactive BAK monomer to a highly dynamic membrane-associated, pore-forming oligomer.

  •   Dynamic reconfiguration of pro-apoptotic BAK on membranes
    EMBO J. (IF 11.598) Pub Date : 2021-09-15
    Jarrod J Sandow, Iris KL Tan, Alan S Huang, Shashank Masaldan, Jonathan P Bernardini, Ahmad Z Wardak, Richard W Birkinshaw, Robert L Ninnis, Ziyan Liu, Destiny Dalseno, Daisy Lio, Giuseppi Infusini, Peter E Czabotar, Andrew I Webb, Grant Dewson

    BAK and BAX, the effectors of intrinsic apoptosis, each undergo major reconfiguration to an activated conformer that self-associates to damage mitochondria and cause cell death. However, the dynamic structural mechanisms of this reconfiguration in the presence of a membrane have yet to be fully elucidated. To explore the metamorphosis of membrane-bound BAK, we employed hydrogen-deuterium exchange mass

  •   High-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane
    EMBO J. (IF 11.598) Pub Date : 2021-09-15
    Laura E Sperl, Florian Rührnößl, Anita Schiller, Martin Haslbeck, Franz Hagn

    Permeabilization of the outer mitochondrial membrane by pore-forming Bcl2 proteins is a crucial step for the induction of apoptosis. Despite a large set of data suggesting global conformational changes within pro-apoptotic Bak during pore formation, high-resolution structural details in a membrane environment remain sparse. Here, we used NMR and HDX-MS (Hydrogen deuterium exchange mass spectrometry)

  •   Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans
    EMBO J. (IF 11.598) Pub Date : 2021-09-23
    Marta Bermejo-Jambrina, Julia Eder, Tanja M Kaptein, John L van Hamme, Leanne C Helgers, Killian E Vlaming, Philip J M Brouwer, Ad C van Nuenen, Marcel Spaargaren, Godelieve J de Bree, Bernadien M Nijmeijer, Neeltje A Kootstra, Marit J van Gils, Rogier W Sanders, Teunis B H Geijtenbeek

    The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans

  •   GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis
    EMBO J. (IF 11.598) Pub Date : 2021-09-13
    Prathyush Pothukuchi, Ilenia Agliarulo, Marinella Pirozzi, Riccardo Rizzo, Domenico Russo, Gabriele Turacchio, Julian Nüchel, Jia-Shu Yang, Charlotte Gehin, Laura Capolupo, Maria Jose Hernandez-Corbacho, Ansuman Biswas, Giovanna Vanacore, Nina Dathan, Takahiro Nitta, Petra Henklein, Mukund Thattai, Jin-Ichi Inokuchi, Victor W Hsu, Markus Plomann, Lina M Obeid, Yusuf A Hannun, Alberto Luini, Giovanni

    The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55

  •   Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast
    EMBO J. (IF 11.598) Pub Date : 2021-09-14
    Xue Bao, Martijn C Koorengevel, Marian J A Groot Koerkamp, Amir Homavar, Amrah Weijn, Stefan Crielaard, Mike F Renne, Joseph H Lorent, Willie JC Geerts, Michal A Surma, Muriel Mari, Frank C P Holstege, Christian Klose, Anton I P M de Kroon

    Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes, including yeast, and has been assigned multiple functions in addition to acting as building block of the lipid bilayer. Here, by isolating S. cerevisiae suppressor mutants that exhibit robust growth in the absence of PC, we show that PC essentiality is subject to cellular evolvability in yeast. The requirement for

  •   The glycine arginine-rich domain of the RNA-binding protein nucleolin regulates its subcellular localization
    EMBO J. (IF 11.598) Pub Date : 2021-09-13
    Ella Doron-Mandel, Indrek Koppel, Ofri Abraham, Ida Rishal, Terika P Smith, Courtney N Buchanan, Pabitra K Sahoo, Jan Kadlec, Juan A Oses-Prieto, Riki Kawaguchi, Stefanie Alber, Eitan Erez Zahavi, Pierluigi Di Matteo, Agostina Di Pizio, Didi-Andreas Song, Nataliya Okladnikov, Dalia Gordon, Shifra Ben-Dor, Rebecca Haffner-Krausz, Giovanni Coppola, Alma L Burlingame, Pavel Jungwirth, Jeffery L Twiss

    Nucleolin is a multifunctional RNA Binding Protein (RBP) with diverse subcellular localizations, including the nucleolus in all eukaryotic cells, the plasma membrane in tumor cells, and the axon in neurons. Here we show that the glycine arginine rich (GAR) domain of nucleolin drives subcellular localization via protein-protein interactions with a kinesin light chain. In addition, GAR sequences mediate

  •   RASSF1C oncogene elicits amoeboid invasion, cancer stemness, and extracellular vesicle release via a SRC/Rho axis
    EMBO J. (IF 11.598) Pub Date : 2021-09-17
    Maria Laura Tognoli, Nikola Vlahov, Sander Steenbeek, Anna M Grawenda, Michael Eyres, David Cano-Rodriguez, Simon Scrace, Christiana Kartsonaki, Alex von Kriegsheim, Eduard Willms, Matthew J Wood, Marianne G Rots, Jacco van Rheenen, Eric O'Neill, Daniela Pankova

    Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C

  •   CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma
    EMBO J. (IF 11.598) Pub Date : 2021-09-06
    Smitha Sivapragasam, Bastian Stark, Amanda V Albrecht, Kaitlynne A Bohm, Peng Mao, Raymond G Emehiser, Steven A Roberts, Patrick J Hrdlicka, Gregory M K Poon, John J Wyrick

    Somatic mutations in DNA-binding sites for CCCTC-binding factor (CTCF) are significantly elevated in many cancers. Prior analysis has suggested that elevated mutation rates at CTCF-binding sites in skin cancers are a consequence of the CTCF-cohesin complex inhibiting repair of UV damage. Here, we show that CTCF binding modulates the formation of UV damage to induce mutation hot spots. Analysis of genome-wide

  •   Single-cell transcriptomics of suprachiasmatic nuclei reveal a Prokineticin-driven circadian network
    EMBO J. (IF 11.598) Pub Date : 2021-09-06
    Emma L Morris, Andrew P Patton, Johanna E Chesham, Alastair Crisp, Antony Adamson, Michael H Hastings

    Circadian rhythms in mammals are governed by the hypothalamic suprachiasmatic nucleus (SCN), in which 20,000 clock cells are connected together into a powerful time-keeping network. In the absence of network-level cellular interactions, the SCN fails as a clock. The topology and specific roles of its distinct cell populations (nodes) that direct network functions are, however, not understood. To characterise

  •   Lipid metabolism: new twists to the Yin and Yang of PKM2 in cancer
    EMBO J. (IF 11.598) Pub Date : 2021-10-12
    Ali Khateb, Ze’ev A Ronai

    While canonical and non-canonical functions of pyruvate kinase M2 (PKM2) are recognized to mediate often-opposing roles in cancer, its contribution to cellular and systemic fatty acid homeostasis remains poorly understood. A new study by Liu et al (2021) uncovers ER transmembrane protein TMEM33 as a novel target of PKM2, which is essential for regulation of cancer cell cholesterol metabolism. These

  •   A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains
    EMBO J. (IF 11.598) Pub Date : 2021-10-12
    Masafumi Shimojo, Maiko Ono, Hiroyuki Takuwa, Koki Mimura, Yuji Nagai, Masayuki Fujinaga, Tatsuya Kikuchi, Maki Okada, Chie Seki, Masaki Tokunaga, Jun Maeda, Yuhei Takado, Manami Takahashi, Takeharu Minamihisamatsu, Ming-Rong Zhang, Yutaka Tomita, Norihiro Suzuki, Anton Maximov, Tetsuya Suhara, Takafumi Minamimoto, Naruhiko Sahara, Makoto Higuchi

    Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy

  •   The extracellular vesicle generation paradox: a bacterial point of view
    EMBO J. (IF 11.598) Pub Date : 2021-10-11
    Hannah M McMillan, Meta J Kuehn

    All bacteria produce secreted vesicles that carry out a variety of important biological functions. These extracellular vesicles can improve adaptation and survival by relieving bacterial stress and eliminating toxic compounds, as well as by facilitating membrane remodeling and ameliorating inhospitable environments. However, vesicle production comes with a price. It is energetically costly and, in

  •   Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease
    EMBO J. (IF 11.598) Pub Date : 2021-10-07
    Roman Sankowski, Jasmin Ahmari, Charlotte Mezö, Anna Lena Hrabě de Angelis, Vidmante Fuchs, Olaf Utermöhlen, Thorsten Buch, Thomas Blank, Mercedes Gomez de Agüero, Andrew J Macpherson, Daniel Erny

    The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular, and choroid plexus macrophages (collectively called CNS-associated macrophages, CAMs). While previous work has shown that microglial properties depend on environmental signals from the commensal microbiota, the effects of microbiota on CAMs are unknown. By combining

  •   The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation
    EMBO J. (IF 11.598) Pub Date : 2021-10-07
    Anita Pras, Bert Houben, Francesco A Aprile, Renée Seinstra, Rodrigo Gallardo, Leen Janssen, Wytse Hogewerf, Christian Gallrein, Matthias De Vleeschouwer, Alejandro Mata-Cabana, Mandy Koopman, Esther Stroo, Minke de Vries, Samantha Louise Edwards, Janine Kirstein, Michele Vendruscolo, Salvatore Fabio Falsone, Frederic Rousseau, Joost Schymkowitz, Ellen A A Nollen

    While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with

  •   Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
    EMBO J. (IF 11.598) Pub Date : 2021-10-07
    Javier Robles-Valero, Lucía Fernández-Nevado, L Francisco Lorenzo-Martín, Myriam Cuadrado, Isabel Fernández-Pisonero, Sonia Rodríguez-Fdez, Elsa N Astorga-Simón, Antonio Abad, Rubén Caloto, Xosé R Bustelo

    Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional

  •   MARCO+ lymphatic endothelial cells sequester arthritogenic alphaviruses to limit viremia and viral dissemination
    EMBO J. (IF 11.598) Pub Date : 2021-10-07
    Kathryn S Carpentier, Ryan M Sheridan, Cormac J Lucas, Bennett J Davenport, Frances S Li, Erin D Lucas, Mary K McCarthy, Glennys V Reynoso, Nicholas A May, Beth A J Tamburini, Jay R Hesselberth, Heather D Hickman, Thomas E Morrison

    Viremia in the vertebrate host is a major determinant of arboviral reservoir competency, transmission efficiency, and disease severity. However, immune mechanisms that control arboviral viremia are poorly defined. Here, we identify critical roles for the scavenger receptor MARCO in controlling viremia during arthritogenic alphavirus infections in mice. Following subcutaneous inoculation, arthritogenic

  •   Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex
    EMBO J. (IF 11.598) Pub Date : 2021-10-06
    Dimitrios Papagiannidis, Peter W Bircham, Christian Lüchtenborg, Oliver Pajonk, Giulia Ruffini, Britta Brügger, Sebastian Schuck

    Cells dynamically adapt organelle size to current physiological demand. Organelle growth requires membrane biogenesis and therefore needs to be coordinated with lipid metabolism. The endoplasmic reticulum (ER) can undergo massive expansion, but the underlying regulatory mechanisms are largely unclear. Here, we describe a genetic screen for factors involved in ER membrane expansion in budding yeast

  •   A dual-function RNA balances carbon uptake and central metabolism in Vibrio cholerae
    EMBO J. (IF 11.598) Pub Date : 2021-10-06
    Kavyaa Venkat, Mona Hoyos, James RJ Haycocks, Liam Cassidy, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Andreas Tholey, David C Grainger, Kai Papenfort

    Bacterial small RNAs (sRNAs) are well known to modulate gene expression by base pairing with trans-encoded transcripts and are typically non-coding. However, several sRNAs have been reported to also contain an open reading frame and thus are considered dual-function RNAs. In this study, we discovered a dual-function RNA from Vibrio cholerae, called VcdRP, harboring a 29 amino acid small protein (VcdP)

  •   Regulated splicing of large exons is linked to phase-separation of vertebrate transcription factors
    EMBO J. (IF 11.598) Pub Date : 2021-10-04
    Toshihiko Kawachi, Akio Masuda, Yoshihiro Yamashita, Jun-ichi Takeda, Bisei Ohkawara, Mikako Ito, Kinji Ohno

    Although large exons cannot be readily recognized by the spliceosome, many are evolutionarily conserved and constitutively spliced for inclusion in the processed transcript. Furthermore, whether large exons may be enriched in a certain subset of proteins, or mediate specific functions, has remained unclear. Here, we identify a set of nearly 3,000 SRSF3-dependent large constitutive exons (S3-LCEs) in

  •   CDKL5 kinase controls transcription-coupled responses to DNA damage
    EMBO J. (IF 11.598) Pub Date : 2021-10-04
    Taran Khanam, Ivan Muñoz, Florian Weiland, Thomas Carroll, Michael Morgan, Barbara N Borsos, Vasiliki Pantazi, Meghan Slean, Miroslav Novak, Rachel Toth, Paul Appleton, Tibor Pankotai, Houjiang Zhou, John Rouse

    Mutations in the gene encoding the CDKL5 kinase are among the most common genetic causes of childhood epilepsy and can also give rise to the severe neurodevelopmental condition CDD (CDKL5 deficiency disorder). Despite its importance for human health, the phosphorylation targets and cellular roles of CDKL5 are poorly understood, especially in the cell nucleus. Here, we report that CDKL5 is recruited

  •   Epistasis, aneuploidy, and functional mutations underlie evolution of resistance to induced microtubule depolymerization
    EMBO J. (IF 11.598) Pub Date : 2021-10-04
    Mattia Pavani, Paolo Bonaiuti, Elena Chiroli, Fridolin Gross, Federica Natali, Francesca Macaluso, Ádám Póti, Sebastiano Pasqualato, Zoltán Farkas, Simone Pompei, Marco Cosentino Lagomarsino, Giulia Rancati, Dávid Szüts, Andrea Ciliberto

    Cells with blocked microtubule polymerization are delayed in mitosis, but eventually manage to proliferate despite substantial chromosome missegregation. While several studies have analyzed the first cell division after microtubule depolymerization, we have asked how cells cope long-term with microtubule impairment. We allowed 24 clonal populations of yeast cells with beta-tubulin mutations preventing

  •   Autophagy in major human diseases
    EMBO J. (IF 11.598) Pub Date : 2021-08-30
    Daniel J Klionsky, Giulia Petroni, Ravi K Amaravadi, Eric H Baehrecke, Andrea Ballabio, Patricia Boya, José Manuel Bravo-San Pedro, Ken Cadwell, Francesco Cecconi, Augustine M K Choi, Mary E Choi, Charleen T Chu, Patrice Codogno, Maria Isabel Colombo, Ana Maria Cuervo, Vojo Deretic, Ivan Dikic, Zvulun Elazar, Eeva-Liisa Eskelinen, Gian Maria Fimia, David A Gewirtz, Douglas R Green, Malene Hansen, Marja

    Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to

  •   Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolerant nanobodies
    EMBO J. (IF 11.598) Pub Date : 2021-08-09
    Thomas Güttler, Metin Aksu, Antje Dickmanns, Kim M. Stegmann, Kathrin Gregor, Renate Rees, Waltraud Taxer, Oleh Rymarenko, Jürgen Schünemann, Christian Dienemann, Philip Gunkel, Bianka Mussil, Jens Krull, Ulrike Teichmann, Uwe Groß, Volker C Cordes, Matthias Dobbelstein, Dirk Görlich

    Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19. However, their production in mammalian cells is not scalable to meet the global demand. Single-domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein, we isolated

  •   Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites
    EMBO J. (IF 11.598) Pub Date : 2021-08-23
    David Hoffmann, Stefan Mereiter, Yoo Jin Oh, Vanessa Monteil, Elizabeth Elder, Rong Zhu, Daniel Canena, Lisa Hain, Elisabeth Laurent, Clemens Grünwald-Gruber, Miriam Klausberger, Gustav Jonsson, Max J Kellner, Maria Novatchkova, Melita Ticevic, Antoine Chabloz, Gerald Wirnsberger, Astrid Hagelkruys, Friedrich Altmann, Lukas Mach, Johannes Stadlmann, Chris Oostenbrink, Ali Mirazimi, Peter Hinterdorfer

    New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike

  •   Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex
    EMBO J. (IF 11.598) Pub Date : 2021-08-25
    Fabio Da Silva, Kaiqing Zhang, Anneline Pinson, Edoardo Fatti, Michaela Wilsch-Bräuninger, Jessica Herbst, Valerie Vidal, Andreas Schedl, Wieland B Huttner, Christof Niehrs

    The role of WNT/β-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/β-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice

  •   NDST3 deacetylates α-tubulin and suppresses V-ATPase assembly and lysosomal acidification
    EMBO J. (IF 11.598) Pub Date : 2021-08-25
    Qing Tang, Mingming Liu, Yang Liu, Ran-Der Hwang, Tao Zhang, Jiou Wang

    Lysosomes are key organelles maintaining cellular homeostasis in health and disease. Here, we report the identification of N-deacetylase and N-sulfotransferase 3 (NDST3) as a potent regulator of lysosomal functions through an unbiased genetic screen. NDST3 constitutes a new member of the histone deacetylase (HDAC) family and catalyzes the deacetylation of α-tubulin. Loss of NDST3 promotes assembly

  •   A Brucella effector modulates the Arf6-Rab8a GTPase cascade to promote intravacuolar replication
    EMBO J. (IF 11.598) Pub Date : 2021-08-23
    Elizabeth Borghesan, Erin P Smith, Sebenzile Myeni, Kelsey Binder, Leigh A Knodler, Jean Celli

    Remodeling of host cellular membrane transport pathways is a common pathogenic trait of many intracellular microbes that is essential to their intravacuolar life cycle and proliferation. The bacterium Brucella abortus generates a host endoplasmic reticulum-derived vacuole (rBCV) that supports its intracellular growth, via VirB Type IV secretion system-mediated delivery of effector proteins, whose functions

  •   Role of endopeptidases in peptidoglycan synthesis mediated by alternative cross-linking enzymes in Escherichia coli
    EMBO J. (IF 11.598) Pub Date : 2021-08-12
    Henri Voedts, Delphine Dorchêne, Adam Lodge, Waldemar Vollmer, Michel Arthur, Jean-Emmanuel Hugonnet

    Bacteria resist to the turgor pressure of the cytoplasm through a net-like macromolecule, the peptidoglycan, made of glycan strands connected via peptides cross-linked by penicillin-binding proteins (PBPs). We recently reported the emergence of β-lactam resistance resulting from a bypass of PBPs by the YcbB L,D-transpeptidase (LdtD), which form chemically distinct 3→3 cross-links compared to 4→3 formed

  •   Mechanism of transcription initiation and primer generation at the mitochondrial replication origin OriL
    EMBO J. (IF 11.598) Pub Date : 2021-08-23
    Azadeh Sarfallah, Angelica Zamudio-Ochoa, Michael Anikin, Dmitry Temiakov

    The intricate process of human mtDNA replication requires the coordinated action of both transcription and replication machineries. Transcription and replication events at the lagging strand of mtDNA prompt the formation of a stem-loop structure (OriL) and the synthesis of a ∼25 nt RNA primer by mitochondrial RNA polymerase (mtRNAP). The mechanisms by which mtRNAP recognizes OriL, initiates transcription

  •   SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation
    EMBO J. (IF 11.598) Pub Date : 2021-08-30
    Zihan Zhang, Xiaoping Liu, Lei Li, Yang Yang, Jianguo Yang, Yue Wang, Jiajing Wu, Xiaodi Wu, Lin Shan, Fei Pei, Jianying Liu, Shu Wang, Wei Li, Luyang Sun, Jing Liang, Yongfeng Shang

    Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic

  •   Msps governs acentrosomal microtubule assembly and reactivation of quiescent neural stem cells
    EMBO J. (IF 11.598) Pub Date : 2021-08-09
    Qiannan Deng, Ye Sing Tan, Liang Yuh Chew, Hongyan Wang

    The ability of stem cells to switch between quiescence and proliferation is crucial for tissue homeostasis and regeneration. Drosophila quiescent neural stem cells (NSCs) extend a primary cellular protrusion from the cell body prior to their reactivation. However, the structure and function of this protrusion are not well established. Here, we show that in the protrusion of quiescent NSCs, microtubules

  •   Multi-modal adaptor-clathrin contacts drive coated vesicle assembly
    EMBO J. (IF 11.598) Pub Date : 2021-09-06
    Sarah M Smith, Gabrielle Larocque, Katherine M Wood, Kyle L Morris, Alan M Roseman, Richard B Sessions, Stephen J Royle, Corinne J Smith

    Clathrin-coated pits are formed by the recognition of membrane and cargo by the AP2 complex and the subsequent recruitment of clathrin triskelia. A role for AP2 in coated-pit assembly beyond initial clathrin recruitment has not been explored. Clathrin binds the β2 subunit of AP2, and several binding sites have been identified, but our structural knowledge of these interactions is incomplete and their

  •   Cryo-EM analysis provides new mechanistic insight into ATP binding to Ca2+-ATPase SERCA2b
    EMBO J. (IF 11.598) Pub Date : 2021-08-30
    Yuxia Zhang, Satoshi Watanabe, Akihisa Tsutsumi, Hiroshi Kadokura, Masahide Kikkawa, Kenji Inaba

    Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2b is a ubiquitous SERCA family member that conducts Ca2+ uptake from the cytosol to the ER. Herein, we present a 3.3 Å resolution cryo-electron microscopy (cryo-EM) structure of human SERCA2b in the E1·2Ca2+ state, revealing a new conformation for Ca2+-bound SERCA2b with a much closer arrangement of cytosolic domains than in the previously reported crystal

  •   Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease
    EMBO J. (IF 11.598) Pub Date : 2021-08-19
    Sonja Blumenstock, Elena Katharina Schulz-Trieglaff, Kerstin Voelkl, Anna-Lena Bolender, Paul Lapios, Jana Lindner, Mark S Hipp, F Ulrich Hartl, Rüdiger Klein, Irina Dudanova

    The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack

  •   The CRL4DCAF1 cullin-RING ubiquitin ligase is activated following a switch in oligomerization state
    EMBO J. (IF 11.598) Pub Date : 2021-09-30
    Weaam I Mohamed, Andreas D Schenk, Georg Kempf, Simone Cavadini, Anja Basters, Alessandro Potenza, Wassim Abdul Rahman, Julius Rabl, Kurt Reichermeier, Nicolas H Thomä

    The cullin-4-based RING-type (CRL4) family of E3 ubiquitin ligases functions together with dedicated substrate receptors. Out of the ˜29 CRL4 substrate receptors reported, the DDB1- and CUL4-associated factor 1 (DCAF1) is essential for cellular survival and growth, and its deregulation has been implicated in tumorigenesis. We carried out biochemical and structural studies to examine the structure and

  •   DNA asymmetry promotes SUMO modification of the single-stranded DNA-binding protein RPA
    EMBO J. (IF 11.598) Pub Date : 2021-09-29
    Laurent Cappadocia, Tomasz Kochańczyk, Christopher D Lima

    Repair of DNA double-stranded breaks by homologous recombination (HR) is dependent on DNA end resection and on post-translational modification of repair factors. In budding yeast, single-stranded DNA is coated by replication protein A (RPA) following DNA end resection, and DNA–RPA complexes are then SUMO-modified by the E3 ligase Siz2 to promote repair. Here, we show using enzymatic assays that DNA

  •   Phospholipid-flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure
    EMBO J. (IF 11.598) Pub Date : 2021-09-29
    Tao Li, Diankun Yu, Hayeon C Oak, Beika Zhu, Li Wang, Xueqiao Jiang, Robert S Molday, Arnold Kriegstein, Xianhua Piao

    Synaptic refinement is a critical physiological process that removes excess synapses to establish and maintain functional neuronal circuits. Recent studies have shown that focal exposure of phosphatidylserine (PS) on synapses acts as an “eat me” signal to mediate synaptic pruning. However, the molecular mechanism underlying PS externalization at synapses remains elusive. Here, we find that murine CDC50A

  •   DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis
    EMBO J. (IF 11.598) Pub Date : 2021-09-29
    Mirjam A Beck, Heinz Fischer, Lisa M Grabner, Tamara Groffics, Mircea Winter, Simone Tangermann, Tina Meischel, Barbara Zaussinger-Haas, Patrick Wagner, Carina Fischer, Christina Folie, Julia Arand, Christian Schöfer, Bernard Ramsahoye, Sabine Lagger, Georg Machat, Gregor Eisenwort, Stephanie Schneider, Alexandra Podhornik, Michael Kothmayer, Ursula Reichart, Martin Glösmann, Ido Tamir, Michael Mildner

    DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune

  •   AMPK CA(R)Sts a new light on amino acid sensing
    EMBO J. (IF 11.598) Pub Date : 2021-09-28
    Kristin K Brown

    AMP-activated protein kinase (AMPK) is recognized as a critical regulator of cellular energy metabolism impacted by AMP/ATP and ADP/ATP ratios, or glucose- and fatty acid-derived metabolites. However, its ability to sense alterations in amino acid levels is poorly understood. Recent work by Yuan et al (2021) identifies a novel mechanism of AMPK regulation responsive to changes in availability of the

  •   A regulatory phosphorylation site on Mec1 controls chromatin occupancy of RNA polymerases during replication stress
    EMBO J. (IF 11.598) Pub Date : 2021-09-27
    Verena Hurst, Kiran Challa, Felix Jonas, Romain Forey, Ragna Sack, Jan Seebacher, Christoph D Schmid, Naama Barkai, Kenji Shimada, Susan M Gasser, Jérôme Poli

    Upon replication stress, budding yeast checkpoint kinase Mec1ATR triggers the downregulation of transcription, thereby reducing the level of RNA polymerase (RNAP) on chromatin to facilitate replication fork progression. Here, we identify a hydroxyurea-induced phosphorylation site on Mec1, Mec1-S1991, that contributes to the eviction of RNAPII and RNAPIII during replication stress. The expression of

  •   Some viruses need to phase-separate to replicate
    EMBO J. (IF 11.598) Pub Date : 2021-09-27
    Christopher H Lee, Terence S Dermody

    Replication of rotavirus, an important cause of gastroenteritis in children, proceeds in large, easily discernible cytoplasmic structures, called viroplasms or viral factories, but mechanisms underlying their formation and function in infected cells have remained mysterious. In this issue, Geiger et al (2021) used a combination of in silico, in vitro, and cell-based approaches to define how two essential

  •   Developmental programming and lineage branching of early human telencephalon
    EMBO J. (IF 11.598) Pub Date : 2021-09-24
    Lin Ma, Yanhua Du, Yi Hui, Nan Li, Beibei Fan, Xiaojie Zhang, Xiaocui Li, Wei Hong, Zhiping Wu, Shuwei Zhang, Shanshan Zhou, Xiangjie Xu, Zhongshu Zhou, Cizhong Jiang, Ling Liu, Xiaoqing Zhang

    The dorsal and ventral human telencephalons contain different neuronal subtypes, including glutamatergic, GABAergic, and cholinergic neurons, and how these neurons are generated during early development is not well understood. Using scRNA-seq and stringent validations, we reveal here a developmental roadmap for human telencephalic neurons. Both dorsal and ventral telencephalic radial glial cells (RGs)

  •   Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4
    EMBO J. (IF 11.598) Pub Date : 2021-09-22
    Stefanie Ohlig, Solène Clavreul, Manja Thorwirth, Tatiana Simon-Ebert, Riccardo Bocchi, Sabine Ulbricht, Nirmal Kannayian, Moritz Rossner, Swetlana Sirko, Pawel Smialowski, Judith Fischer-Sternjak, Magdalena Götz

    Astrocytes regulate brain-wide functions and also show region-specific differences, but little is known about how general and region-specific functions are aligned at the single-cell level. To explore this, we isolated adult mouse diencephalic astrocytes by ACSA-2-mediated magnetic-activated cell sorting (MACS). Single-cell RNA-seq revealed 7 gene expression clusters of astrocytes, with 4 forming a

  •   Ablation of mitochondrial DNA results in widespread remodeling of the mitochondrial complexome
    EMBO J. (IF 11.598) Pub Date : 2021-09-20
    Sergio Guerrero-Castillo, Joeri van Strien, Ulrich Brandt, Susanne Arnold

    So-called ρ0 cells lack mitochondrial DNA and are therefore incapable of aerobic ATP synthesis. How cells adapt to survive ablation of oxidative phosphorylation remains poorly understood. Complexome profiling analysis of ρ0 cells covered 1,002 mitochondrial proteins and revealed changes in abundance and organization of numerous multiprotein complexes including previously not described assemblies. Beyond

  •   DNA polymerase zeta contributes to heterochromatin replication to prevent genome instability
    EMBO J. (IF 11.598) Pub Date : 2021-09-17
    Barbara Ben Yamin, Sana Ahmed-Seghir, Junya Tomida, Emmanuelle Despras, Caroline Pouvelle, Andrey Yurchenko, Jordane Goulas, Raphael Corre, Quentin Delacour, Nathalie Droin, Philippe Dessen, Didier Goidin, Sabine S Lange, Sarita Bhetawal, Maria Teresa Mitjavila-Garcia, Giuseppe Baldacci, Sergey Nikolaev, Jean Charles Cadoret, Richard D Wood, Patricia L Kannouche

    The DNA polymerase zeta (Polζ) plays a critical role in bypassing DNA damage. REV3L, the catalytic subunit of Polζ, is also essential in mouse embryonic development and cell proliferation for reasons that remain incompletely understood. In this study, we reveal that REV3L protein interacts with heterochromatin components including repressive histone marks and localizes in pericentromeric regions through

  •   Non-genetic and genetic rewiring underlie adaptation to hypomorphic alleles of an essential gene
    EMBO J. (IF 11.598) Pub Date : 2021-09-15
    Altea Targa, Katherine E Larrimore, Cheng Kit Wong, Yu Lin Chong, Ronald Fung, Joseph Lee, Hyungwon Choi, Giulia Rancati

    Adaptive evolution to cellular stress is a process implicated in a wide range of biological and clinical phenomena. Two major routes of adaptation have been identified: non-genetic changes, which allow expression of different phenotypes in novel environments, and genetic variation achieved by selection of fitter phenotypes. While these processes are broadly accepted, their temporal and epistatic features

  •   MtNPF6.5 mediates chloride uptake and nitrate preference in Medicago roots
    EMBO J. (IF 11.598) Pub Date : 2021-09-15
    Qiying Xiao, Yi Chen, Cheng-Wu Liu, Fran Robson, Sonali Roy, Xiaofei Cheng, Jiangqi Wen, Kirankumar Mysore, Anthony J Miller, Jeremy D Murray

    The preference for nitrate over chloride through regulation of transporters is a fundamental feature of plant ion homeostasis. We show that Medicago truncatula MtNPF6.5, an ortholog of Arabidopsis thaliana AtNPF6.3/NRT1.1, can mediate nitrate and chloride uptake in Xenopus oocytes but is chloride selective and that its close homologue, MtNPF6.7, can transport nitrate and chloride but is nitrate selective

  •   Liquid–liquid phase separation underpins the formation of replication factories in rotaviruses
    EMBO J. (IF 11.598) Pub Date : 2021-09-15
    Florian Geiger, Julia Acker, Guido Papa, Xinyu Wang, William E Arter, Kadi L Saar, Nadia A Erkamp, Runzhang Qi, Jack PK Bravo, Sebastian Strauss, Georg Krainer, Oscar R Burrone, Ralf Jungmann, Tuomas PJ Knowles, Hanna Engelke, Alexander Borodavka

    RNA viruses induce the formation of subcellular organelles that provide microenvironments conducive to their replication. Here we show that replication factories of rotaviruses represent protein-RNA condensates that are formed via liquid–liquid phase separation of the viroplasm-forming proteins NSP5 and rotavirus RNA chaperone NSP2. Upon mixing, these proteins readily form condensates at physiologically

  •   Cancer evolution: Darwin and beyond
    EMBO J. (IF 11.598) Pub Date : 2021-08-30
    Roberto Vendramin, Kevin Litchfield, Charles Swanton

    Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome

  •   Dynamic EMT: a multi-tool for tumor progression
    EMBO J. (IF 11.598) Pub Date : 2021-08-30
    Simone Brabletz, Harald Schuhwerk, Thomas Brabletz, Marc P. Stemmler

    The process of epithelial–mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety

  •   Host autophagy mediates organ wasting and nutrient mobilization for tumor growth
    EMBO J. (IF 11.598) Pub Date : 2021-07-26
    Rojyar Khezri, Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten

    During tumor growth—when nutrient and anabolic demands are high—autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ

  •   Desensitisation of Notch signalling through dynamic adaptation in the nucleus
    EMBO J. (IF 11.598) Pub Date : 2021-08-16
    Ranjith Viswanathan, Jonas Hartmann, Cristina Pallares Cartes, Stefano De Renzis

    During embryonic development, signalling pathways orchestrate organogenesis by controlling tissue-specific gene expression programmes and differentiation. Although the molecular components of many common developmental signalling systems are known, our current understanding of how signalling inputs are translated into gene expression outputs in real-time is limited. Here we employ optogenetics to control

  •   SARS-CoV-2 nucleocapsid suppresses host pyroptosis by blocking Gasdermin D cleavage
    EMBO J. (IF 11.598) Pub Date : 2021-08-04
    Juan Ma, Fangrui Zhu, Min Zhao, Fei Shao, Dou Yu, Jiangwen Ma, Xusheng Zhang, Weitao Li, Yan Qian, Yan Zhang, Dong Jiang, Shuo Wang, Pengyan Xia

    SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by

  •   Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection
    EMBO J. (IF 11.598) Pub Date : 2021-08-02
    Jyoti Batra, Hiroyuki Mori, Gabriel I Small, Manu Anantpadma, Olena Shtanko, Nawneet Mishra, Mengru Zhang, Dandan Liu, Caroline G Williams, Nadine Biedenkopf, Stephan Becker, Michael L Gross, Daisy W Leung, Robert A Davey, Gaya K Amarasinghe, Nevan J Krogan, Christopher F Basler

    The Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs that adopt non-canonical orientations, as compared to other proline-rich motifs. An affinity tag-purification mass spectrometry approach identified additional PPxPxY-containing host proteins hnRNP L, hnRNPUL1, and PEG10, as VP30 interactors. hnRNP L and PEG10, like RBBP6, inhibit viral

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