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  • Loss of MT1‐MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
    Loss of MT1‐MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
    1. Ana Gutiérrez‐Fernández1,
    2. Clara Soria‐Valles1,
    3. Fernando G Osorio1,
    4. Jesús Gutiérrez‐Abril1,
    5. Cecilia Garabaya1,
    6. Alina Aguirre2,
    7. Antonio Fueyo2,
    8. María Soledad Fernández‐García3,
    9. Xose S Puente1 and
    10. Carlos López‐Otín*,1
    1. 1Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain
    2. 2Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain
    3. 3Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain
    1. *Corresponding author. Tel: +34 985 104 201; Fax: +34 985 103 564; E‐mail: clo{at}uniovi.es

    Alterations in the extracellular matrix caused by loss of protease MT1‐MMP lead to cellular senescence, nuclear lamina abnormalities, and features of premature ageing that can be rescued by treatment with retinoic acid.

    Synopsis

    Alterations in the extracellular matrix caused by loss of protease MT1‐MMP lead to cellular senescence, nuclear lamina abnormalities, and features of premature ageing that can be rescued by treatment with retinoic acid.

    • Loss of MT1‐MMP metalloprotease activity induces a cellular senescence phenotype.

    • Deficient remodeling of the extracellular matrix alters the cytoskeleton and nuclear structure.

    • All‐trans retinoic acid treatment ameliorates the cellular senescence process.

    • aging
    • extracellular matrix
    • metalloprotease
    • nuclear lamina
    • retinoids
    • Received November 18, 2014.
    • Revision received April 15, 2015.
    • Accepted April 24, 2015.
    Ana Gutiérrez‐Fernández, Clara Soria‐Valles, Fernando G Osorio, Jesús Gutiérrez‐Abril, Cecilia Garabaya, Alina Aguirre, Antonio Fueyo, María Soledad Fernández‐García, Xose S Puente, Carlos López‐Otín
  • TUT7 controls the fate of precursor microRNAs by using three different uridylation mechanisms
    TUT7 controls the fate of precursor microRNAs by using three different uridylation mechanisms
    1. Boseon Kim1,2,,
    2. Minju Ha1,2,,
    3. Luuk Loeff3,,
    4. Hyeshik Chang1,2,
    5. Dhirendra K Simanshu4,
    6. Sisi Li4,
    7. Mohamed Fareh3,
    8. Dinshaw J Patel4,
    9. Chirlmin Joo*,3 and
    10. V Narry Kim*,1,2
    1. 1Center for RNA Research, Institute for Basic Science, Seoul, Korea
    2. 2School of Biological Sciences, Seoul National University, Seoul, Korea
    3. 3Kavli Institute of NanoScience, Department of BioNanoScience, Delft University of Technology, Delft, The Netherlands
    4. 4Structural Biology Program, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA
    1. * Corresponding author. Tel: +31 15 27 83220; Fax: +31 15 27 81202; E‐mail: c.joo{at}tudelft.nl

      Corresponding author. Tel: +82 2 880 9120; Fax: +82 2 887 0244; E‐mail: narrykim{at}snu.ac.kr

    1. These authors contributed equally to this work

    Uridylation of miRNA precursors can either stimulate processing or trigger RNA degradation. This study shows how RNA overhang structure and the mode of TUTase binding facilitate differential uridylation of specific precursor types.

    Synopsis

    Uridylation of miRNA precursors can either stimulate processing or trigger RNA degradation. This study shows how RNA overhang structure and the mode of TUTase binding facilitate differential uridylation of specific precursor types.

    • Terminal uridylyl transferases (TUTs) exert multiple roles in miRNA biogenesis by uridylating precursor miRNAs, thereby determining their fates.

    • For group II pre‐miRNAs, which carry a 1‐nt 3′ overhang, TUT7/4/2 restore the canonical end structure through mono‐uridylation, promoting miRNA biogenesis.

    • For 3′ trimmed pre‐miRNAs, TUT7/4 distributively generate an oligo‐U tail that triggers degradation.

    • TUT7 distinguishes pre‐miRNA species at the binding step and shows distinct binding frequency to different RNA substrates.

    • precursor microRNA
    • single‐molecule fluorescence
    • TUT4 (ZCCHC11)
    • TUT7 (ZCCHC6)
    • uridylation
    • Received January 2, 2015.
    • Revision received April 5, 2015.
    • Accepted April 8, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Boseon Kim, Minju Ha, Luuk Loeff, Hyeshik Chang, Dhirendra K Simanshu, Sisi Li, Mohamed Fareh, Dinshaw J Patel, Chirlmin Joo, V Narry Kim
  • Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2
    Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2
    1. Stephen G Dann*,1,
    2. Michael Ryskin2,
    3. Anthony M Barsotti2,
    4. Jonathon Golas2,
    5. Celine Shi2,
    6. Miriam Miranda2,
    7. Christine Hosselet2,
    8. Luanna Lemon2,
    9. Judy Lucas2,
    10. Maha Karnoub3,
    11. Fang Wang2,
    12. Jeremy S Myers2,
    13. Scott J Garza1,
    14. Maximillian T Follettie2,
    15. Kenneth G Geles2,
    16. Anke Klippel3,
    17. Robert A Rollins2 and
    18. Valeria R Fantin1
    1. 1Pfizer Oncology Research Unit, San Diego, CA, USA
    2. 2Pfizer Oncology Research Unit, Pearl River, NY, USA
    3. 3Celgene, Summit, NJ, USA
    1. *Corresponding author. Tel: +1 845 602 2370; Fax: +1 845 602 5557; E‐mail: stephen.dann{at}pfizer.com

    The amino acid transporter Lat1 increases cellular S‐adenosylmethionine concentrations and thereby EZH2 activity, and this dictates the differentiation state of cancer cells and tumour growth.

    Synopsis

    A metabolic–epigenetic feedback loop between the methionine transporter Lat1 and the histone methyltransferase EZH2 dictates differentiation state in a malignant context.

    • Cells sorted for high CD98/Lat1 expression contain elevated methionine cycle metabolites and more active EZH2 and are more aggressive in lung cancer models.

    • Amino acid restriction, methionine dropout, or Lat1 shRNA impairs EZH2 activity due to reduction in cellular S‐adenosylmethionine.

    • Lat1 and EZH2 expressions correlate with a less‐differentiated state as illustrated by spheroid models of cancer cell differentiation, retinoic acid‐mediated transcription, and immunohistochemical analysis of human lung cancer.

    • EZH2 activity and PRC2 activity derepress Lat1 expression through direct promoter binding and subsequent transcriptional repression of RXRα.

    • cancer metabolism
    • methionine cycle
    • S‐adenosylmethionine
    • SLC7A5
    • Received February 7, 2014.
    • Revision received April 10, 2015.
    • Accepted April 14, 2015.
    Stephen G Dann, Michael Ryskin, Anthony M Barsotti, Jonathon Golas, Celine Shi, Miriam Miranda, Christine Hosselet, Luanna Lemon, Judy Lucas, Maha Karnoub, Fang Wang, Jeremy S Myers, Scott J Garza, Maximillian T Follettie, Kenneth G Geles, Anke Klippel, Robert A Rollins, Valeria R Fantin
  • Not4‐dependent translational repression is important for cellular protein homeostasis in yeast
    Not4‐dependent translational repression is important for cellular protein homeostasis in yeast
    1. Steffen Preissler*,1,24,
    2. Julia Reuther1,2,,
    3. Miriam Koch1,25,
    4. Annika Scior1,26,
    5. Michael Bruderek17,
    6. Tancred Frickey3 and
    7. Elke Deuerling*,1
    1. 1Molecular Microbiology, University of Konstanz, Konstanz, Germany
    2. 2Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany
    3. 3Applied Bioinformatics, University of Konstanz, Konstanz, Germany
    4. 4University of Cambridge Cambridge Institute for Medical Research, Cambridge, UK
    5. 5 Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
    6. 6 Leibniz‐Institut für Molekulare Pharmakologie, Campus Berlin‐Buch, Berlin, Germany
    7. 7 Institute of Biochemistry and Molecular Biology University of Bonn, Bonn, Germany
    1. * Corresponding author. Tel: +44 1223 769100; E‐mail: sp693{at}cam.ac.uk

      Corresponding author. Tel: +49 7531 882647; E‐mail: elke.deuerling{at}uni-konstanz.de

    1. These authors contributed equally to this work

    Not4, a component of the CCR4‐NOT complex, triggers translational repression of mRNAs carrying transiently stalled ribosomes and contributes to the maintenance of protein homeostasis during cellular stress.

    Synopsis

    Not4, a component of the CCR4‐NOT complex, triggers translational repression of mRNAs carrying transiently stalled ribosomes and contributes to the maintenance of protein homeostasis during cellular stress.

    • Not4 and the Ccr4‐Not complex associate with polysomes.

    • Deletion of NOT4 increases the expression of cotranslationally arrested polypeptides.

    • Not4 loss reduces translational repression upon nutrient withdrawal and triggers severe protein synthesis‐dependent folding stress.

    • Cells with impaired mRNA decapping protein function show similar phenotypes to NOT4 deletion.

    • Not4 and the decapping machinery contribute to the negative regulation of protein synthesis that is important for the maintenance of cellular proteostasis.

    • Ccr4–Not complex
    • Not4
    • protein homeostasis
    • ribosome stalling
    • translational repression
    • Received September 30, 2014.
    • Revision received April 7, 2015.
    • Accepted April 12, 2015.
    Steffen Preissler, Julia Reuther, Miriam Koch, Annika Scior, Michael Bruderek, Tancred Frickey, Elke Deuerling
  • Simply the right time to turn on insulin
    Simply the right time to turn on insulin
    1. Francesca M Spagnoli (francesca.spagnoli{at}mdc-berlin.de) 1
    1. 1Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany

    Recent research has made important progress in the directed differentiation of human pluripotent stem cells into insulin‐producing beta‐like cells in vitro. A new study published in this issue of The EMBO Journal reports that timely induction of NEUROG3 expression in pancreatic progenitors is a crucial checkpoint for generation of functional human beta cells.

    See also: HA Russ et al

    Recent work identifies precise induction of NEUROG3 expression in pancreatic progenitor cells as a crucial checkpoint for generating functional human beta cells.

    Francesca M Spagnoli
  • Poised for action: USP18 restrains microglial activation in the white matter
    Poised for action: USP18 restrains microglial activation in the white matter
    1. Kazuyuki Takata1,2 and
    2. Florent Ginhoux (Florent_Ginhoux{at}immunol.a-star.edu.sg) 1
    1. 1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
    2. 2Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan

    Microglia are the resident macrophage population of the central nervous system (CNS) and are required for CNS development, homeostasis, and immune defense. Dysregulated microglial activity is involved in the pathogenesis of neuro‐degenerative conditions and is the dominant driver of neuro‐inflammatory diseases named “microgliopathies”. In this issue of The EMBO Journal, Goldmann et al reveal that white matter microglia in mice are actively maintained in a quiescent state via the ubiquitin‐specific protease (Usp) 18 (Goldmann et al, 2015). Removing this molecular blocker results in aggressive type I IFN‐mediated pathology, with features reminiscent of human microgliopathy. This study furthers our knowledge of the roles and regulation of microglial populations, adds insight into the processes underlying neuro‐inflammation, and broadens our consideration of immune regulation to include the concept of active restraint as a necessary component to avoid excessive inflammation.

    See also: T Goldmann et al

    Dedicated mechanisms actively maintain CNS macrophages in a quiescent state to avoid constitutive activation and immune pathology.

    Kazuyuki Takata, Florent Ginhoux
  • The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity
    The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐secretase activity
    1. Hyo‐Jin Park1,2,
    2. Yong Ran1,
    3. Joo In Jung1,
    4. Oliver Holmes3,
    5. Ashleigh R Price1,
    6. Lisa Smithson1,
    7. Carolina Ceballos‐Diaz1,
    8. Chul Han4,
    9. Michael S Wolfe3,
    10. Yehia Daaka5,
    11. Andrey E Ryabinin6,
    12. Seong‐Hun Kim2,
    13. Richard L Hauger7,
    14. Todd E Golde*,1 and
    15. Kevin M Felsenstein*,1
    1. 1Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA
    2. 2Department of Pharmacology and Therapeutics, College of Medicine, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
    3. 3Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
    4. 4Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL, USA
    5. 5Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA
    6. 6Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA
    7. 7Center of Excellence for Stress and Mental Health, Department of Psychiatry, VA Healthcare System, University of California, San Diego, CA, USA
    1. * Corresponding author. Tel: +1 352 273 9456; E‐mail: tgolde{at}ufl.edu

      Corresponding author. Tel: +1 352 294 5308; E‐mail: kfelsenstein0{at}ufl.edu

    The critical stress mediator corticotropin releasing factor (CRF) increases amyloid‐β production by altering γ‐secretase localization and activity, thus providing a link between stress and amyloid‐β pathology.

    Synopsis

    Excessive activation of the hypothalamic–pituitary–adrenal (HPA) stress axis may be a risk factor for Alzheimer's disease. Stress exacerbates amyloid‐β (Aβ) accumulation in various animal models. Here we show that:

    • Corticotropin releasing factor (CRF), a critical stress response mediator, increases Aβ production in cells and non‐transgenic mice.

    • γ‐secretase interacts with CRF receptor 1 (CRFR1) through β‐arrestins.

    • Upon CRF binding to CRFR1, γ‐secretase–CRFR1 complex moves into lipid rafts and endosomes where γ‐secretase activity increases.

    • CRF and CRFR antagonists activate γ‐secretase in vitro through CRFR1‐independent mechanisms.

    • β‐arrestin
    • γ‐secretase
    • amyloid‐β
    • corticotrophin releasing factor
    • stress
    • Received April 28, 2014.
    • Revision received April 10, 2015.
    • Accepted April 15, 2015.
    Hyo‐Jin Park, Yong Ran, Joo In Jung, Oliver Holmes, Ashleigh R Price, Lisa Smithson, Carolina Ceballos‐Diaz, Chul Han, Michael S Wolfe, Yehia Daaka, Andrey E Ryabinin, Seong‐Hun Kim, Richard L Hauger, Todd E Golde, Kevin M Felsenstein