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EMBO Journal

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https://www.readbyqxmd.com/read/29335281/high-throughput-identification-of-rna-nuclear-enrichment-sequences
#1
Chinmay J Shukla, Alexandra L McCorkindale, Chiara Gerhardinger, Keegan D Korthauer, Moran N Cabili, David M Shechner, Rafael A Irizarry, Philipp G Maass, John L Rinn
In the post-genomic era, thousands of putative noncoding regulatory regions have been identified, such as enhancers, promoters, long noncoding RNAs (lncRNAs), and a cadre of small peptides. These ever-growing catalogs require high-throughput assays to test their functionality at scale. Massively parallel reporter assays have greatly enhanced the understanding of noncoding DNA elements en masse Here, we present a massively parallel RNA assay (MPRNA) that can assay 10,000 or more RNA segments for RNA-based functionality...
January 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29335280/mapping-protein-interactions-of-sodium-channel-nav1-7-using-epitope-tagged-gene-targeted-mice
#2
Alexandros H Kanellopoulos, Jennifer Koenig, Honglei Huang, Martina Pyrski, Queensta Millet, Stéphane Lolignier, Toru Morohashi, Samuel J Gossage, Maude Jay, John E Linley, Georgios Baskozos, Benedikt M Kessler, James J Cox, Annette C Dolphin, Frank Zufall, John N Wood, Jing Zhao
The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. We generated an epitope-tagged NaV1.7 mouse that showed normal pain behaviours to identify channel-interacting proteins. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 proteins associated with Nav1.7 in vivo The sodium channel β3 (Scn3b), rather than the β1 subunit, complexes with Nav1.7, and we demonstrate an interaction between collapsing-response mediator protein (Crmp2) and Nav1...
January 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29330193/structure-of-the-human-myostatin-precursor-and-determinants-of-growth-factor-latency
#3
Thomas R Cotton, Gerhard Fischer, Xuelu Wang, Jason C McCoy, Magdalena Czepnik, Thomas B Thompson, Marko Hyvönen
Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have determined the structure of unprocessed pro-myostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement. The pro-mature complex, after cleavage of the furin site, has significantly reduced activity compared with the mature growth factor and persists as a stable complex that is resistant to the natural antagonist follistatin...
January 12, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29317426/the-wd40-domain-of-atg16l1-is-required-for-its%C3%A2-non-canonical-role-in-lipidation-of-lc3-at-single%C3%A2-membranes
#4
Katherine Fletcher, Rachel Ulferts, Elise Jacquin, Talitha Veith, Noor Gammoh, Julia M Arasteh, Ulrike Mayer, Simon R Carding, Thomas Wileman, Rupert Beale, Oliver Florey
A hallmark of macroautophagy is the covalent lipidation of LC3 and insertion into the double-membrane phagophore, which is driven by the ATG16L1/ATG5-ATG12 complex. In contrast, non-canonical autophagy is a pathway through which LC3 is lipidated and inserted into single membranes, particularly endolysosomal vacuoles during cell engulfment events such as LC3-associated phagocytosis. Factors controlling the targeting of ATG16L1 to phagophores are dispensable for non-canonical autophagy, for which the mechanism of ATG16L1 recruitment is unknown...
January 9, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29311116/stim1-activation-of-adenylyl-cyclase-6-connects-ca2-and-camp-signaling-during-melanogenesis
#5
Rajender K Motiani, Jyoti Tanwar, Desingu Ayyappa Raja, Ayushi Vashisht, Shivangi Khanna, Sachin Sharma, Sonali Srivastava, Sridhar Sivasubbu, Vivek T Natarajan, Rajesh S Gokhale
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca2+ levels has been uncovered in recent years, the functional significance of ER-PM junctions in non-excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis...
January 8, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29311115/miro-proteins-coordinate-microtubule-and-actin-dependent-mitochondrial-transport-and-distribution
#6
Guillermo López-Doménech, Christian Covill-Cooke, Davor Ivankovic, Els F Halff, David F Sheehan, Rosalind Norkett, Nicol Birsa, Josef T Kittler
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells...
January 8, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29301860/moonlighting-activity-of-the-epigenetic-machinery-restrains-infection
#7
Claude Gutierrez, Yves-Marie Boudehen, Olivier Neyrolles
No abstract text is available yet for this article.
January 4, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29301859/parl-partitions-the-lipid-transfer-protein-stard7-between-the-cytosol-and-mitochondria
#8
Shotaro Saita, Takashi Tatsuta, Philipp A Lampe, Tim König, Yohsuke Ohba, Thomas Langer
Intramembrane-cleaving peptidases of the rhomboid family regulate diverse cellular processes that are critical for development and cell survival. The function of the rhomboid protease PARL in the mitochondrial inner membrane has been linked to mitophagy and apoptosis, but other regulatory functions are likely to exist. Here, we identify the START domain-containing protein STARD7 as an intramitochondrial lipid transfer protein for phosphatidylcholine. We demonstrate that PARL-mediated cleavage during mitochondrial import partitions STARD7 to the cytosol and the mitochondrial intermembrane space...
January 4, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29288164/lrrc25-inhibits-type-i-ifn-signaling-by-targeting-isg15-associated-rig-i-for-autophagic-degradation
#9
Yang Du, Tianhao Duan, Yanchun Feng, Qingxiang Liu, Meng Lin, Jun Cui, Rong-Fu Wang
The RIG-I-like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that leucine-rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR-mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15-associated RIG-I to promote interaction between RIG-I and the autophagic cargo receptor p62 and to mediate RIG-I degradation via selective autophagy...
December 29, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29282206/colonic-epithelium-rejuvenation-through-yap-taz
#10
Rui Chen, Kun-Liang Guan
No abstract text is available yet for this article.
December 27, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29282205/glycosphingolipid-metabolic-reprogramming-drives-neural-differentiation
#11
Domenico Russo, Floriana Della Ragione, Riccardo Rizzo, Eiji Sugiyama, Francesco Scalabrì, Kei Hori, Serena Capasso, Lucia Sticco, Salvatore Fioriniello, Roberto De Gregorio, Ilaria Granata, Mario R Guarracino, Vittorio Maglione, Ludger Johannes, Gian Carlo Bellenchi, Mikio Hoshino, Mitsutoshi Setou, Maurizio D'Esposito, Alberto Luini, Giovanni D'Angelo
Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood...
December 27, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29263148/regulatory-t-cells-constrain-the-tcr-repertoire-of-antigen-stimulated-conventional-cd4-t-cells
#12
Martina Fontaine, Isabel Vogel, Yves-Rémi Van Eycke, Adrien Galuppo, Yousra Ajouaou, Christine Decaestecker, George Kassiotis, Muriel Moser, Oberdan Leo
To analyze the potential role of Tregs in controlling the TCR repertoire breadth to a non-self-antigen, a TCRβ transgenic mouse model (EF4.1) expressing a limited, yet polyclonal naïve T-cell repertoire was used. The response of EF4.1 mice to an I-Ab-associated epitope of the F-MuLV envelope protein is dominated by clones expressing a Vα2 gene segment, thus allowing a comprehensive analysis of the TCRα repertoire in a relatively large cohort of mice. Control and Treg-depleted EF4.1 mice were immunized, and the extent of the Vα2-bearing, antigen-specific TCR repertoire was characterized by high-throughput sequencing and spectratyping analysis...
December 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29255010/cryo-em-reconstruction-of-type-vi-secretion-system-baseplate-and-sheath-distal-end
#13
Sergey Nazarov, Johannes P Schneider, Maximilian Brackmann, Kenneth N Goldie, Henning Stahlberg, Marek Basler
The bacterial Type VI secretion system (T6SS) assembles from three major parts: a membrane complex that spans inner and outer membranes, a baseplate, and a sheath-tube polymer. The baseplate assembles around a tip complex with associated effectors and connects to the membrane complex by TssK. The baseplate assembly initiates sheath-tube polymerization, which in some organisms requires TssA. Here, we analyzed both ends of isolated non-contractile Vibrio cholerae sheaths by cryo-electron microscopy. Our analysis suggests that the baseplate, solved to an average 8...
December 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29247078/high-capacity-of-the-endoplasmic-reticulum-to-prevent-secretion-and-aggregation-of-amyloidogenic-proteins
#14
Lisa Vincenz-Donnelly, Hauke Holthusen, Roman Körner, Erik C Hansen, Jenny Presto, Jan Johansson, Ritwick Sawarkar, F Ulrich Hartl, Mark S Hipp
Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles β-sheet proteins that were designed de novo to form amyloid-like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER-β) strongly reduces their toxicity. ER-β is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones...
December 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29237698/oxys-small-rna-induces-cell-cycle-arrest-to-allow-dna-damage-repair
#15
Shir Barshishat, Maya Elgrably-Weiss, Jonathan Edelstein, Jens Georg, Sutharsan Govindarajan, Meytal Haviv, Patrick R Wright, Wolfgang R Hess, Shoshy Altuvia
To maintain genome integrity, organisms employ DNA damage response, the underlying principles of which are conserved from bacteria to humans. The bacterial small RNA OxyS of Escherichia coli is induced upon oxidative stress and has been implicated in protecting cells from DNA damage; however, the mechanism by which OxyS confers genome stability remained unknown. Here, we revealed an OxyS-induced molecular checkpoint relay, leading to temporary cell cycle arrest to allow damage repair. By repressing the expression of the essential transcription termination factor nusG, OxyS enables read-through transcription into a cryptic prophage encoding kilR The KilR protein interferes with the function of the major cell division protein FtsZ, thus imposing growth arrest...
December 13, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29233834/the-arabidopsis-alf4-protein-is-a-regulator-of-scf-e3-ligases
#16
Rammyani Bagchi, Charles W Melnyk, Gideon Christ, Martin Winkler, Kerstin Kirchsteiner, Mohammad Salehin, Julia Mergner, Michael Niemeyer, Claus Schwechheimer, Luz Irina A Calderón Villalobos, Mark Estelle
The cullin-RING E3 ligases (CRLs) regulate diverse cellular processes in all eukaryotes. CRL activity is controlled by several proteins or protein complexes, including NEDD8, CAND1, and the CSN Recently, a mammalian protein called Glomulin (GLMN) was shown to inhibit CRLs by binding to the RING BOX (RBX1) subunit and preventing binding to the ubiquitin-conjugating enzyme. Here, we show that Arabidopsis ABERRANT LATERAL ROOT FORMATION4 (ALF4) is an ortholog of GLMN The alf4 mutant exhibits a phenotype that suggests defects in plant hormone response...
December 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29229786/seed-induced-a%C3%AE-deposition-is-modulated-by-microglia-under-environmental-enrichment-in-a-mouse-model-of-alzheimer-s-disease
#17
Stephanie Ziegler-Waldkirch, Paolo D Errico, Jonas-Frederic Sauer, Daniel Erny, Shakuntala Savanthrapadian, Desirée Loreth, Natalie Katzmarski, Thomas Blank, Marlene Bartos, Marco Prinz, Melanie Meyer-Luehmann
Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid-β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion-like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models...
December 11, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29222176/ca2-releases-e-syt1-autoinhibition-to-couple-er-plasma-membrane-tethering-with-lipid-transport
#18
Xin Bian, Yasunori Saheki, Pietro De Camilli
The extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER) proteins that bind the plasma membrane (PM) via C2 domains and transport lipids between them via SMP domains. E-Syt1 tethers and transports lipids in a Ca2+-dependent manner, but the role of Ca2+ in this regulation is unclear. Of the five C2 domains of E-Syt1, only C2A and C2C contain Ca2+-binding sites. Using liposome-based assays, we show that Ca2+ binding to C2C promotes E-Syt1-mediated membrane tethering by releasing an inhibition that prevents C2E from interacting with PI(4,5)P2-rich membranes, as previously suggested by studies in semi-permeabilized cells...
December 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29217591/topologically-associating-domains-and-chromatin-loops-depend-on-cohesin-and-are-regulated-by-ctcf-wapl-and-pds5-proteins
#19
Gordana Wutz, Csilla Várnai, Kota Nagasaka, David A Cisneros, Roman R Stocsits, Wen Tang, Stefan Schoenfelder, Gregor Jessberger, Matthias Muhar, M Julius Hossain, Nike Walther, Birgit Koch, Moritz Kueblbeck, Jan Ellenberg, Johannes Zuber, Peter Fraser, Jan-Michael Peters
Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops...
December 7, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29217590/a-mechanism-of-cohesin-dependent-loop-extrusion-organizes-zygotic-genome-architecture
#20
Johanna Gassler, Hugo B Brandão, Maxim Imakaev, Ilya M Flyamer, Sabrina Ladstätter, Wendy A Bickmore, Jan-Michael Peters, Leonid A Mirny, Kikuë Tachibana
Fertilization triggers assembly of higher-order chromatin structure from a condensed maternal and a naïve paternal genome to generate a totipotent embryo. Chromatin loops and domains have been detected in mouse zygotes by single-nucleus Hi-C (snHi-C), but not bulk Hi-C. It is therefore unclear when and how embryonic chromatin conformations are assembled. Here, we investigated whether a mechanism of cohesin-dependent loop extrusion generates higher-order chromatin structures within the one-cell embryo. Using snHi-C of mouse knockout embryos, we demonstrate that the zygotic genome folds into loops and domains that critically depend on Scc1-cohesin and that are regulated in size and linear density by Wapl...
December 7, 2017: EMBO Journal
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