Advertisement

  • Better to burn out than it is to rust: coordinating cellular redox states during aging and stress
    Better to burn out than it is to rust: coordinating cellular redox states during aging and stress
    1. Christopher Rongo (rongo{at}waksman.rutgers.edu)1
    1. 1The Waksman Institute, Department of Genetics, Rutgers The State University of New Jersey, Piscataway, NJ, USA

    Both the protein homeostasis (proteostasis) and the oxidation/reduction (redox) environment of the cell play critical roles in disease‐ and age‐associated decline, yet the relationship between the two remains mysterious. In this issue of The EMBO Journal, Kirstein et al (2015) show that both the cytosol and the ER shift their redox states in response to proteotoxic stress and that stress in one compartment can alter redox state in the other. Moreover, proteotoxic stress can induce changes in redox state across tissues, suggesting that an organism‐wide surveillance mechanism modulates cellular redox environment.

    See also: J Kristein et al

    A recent study showing cytosolic and ER redox states to be inversely regulated upon proteotoxic stress sheds further light on the balance between cellular homeostasis and aging.

    Christopher Rongo
  • Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments
    Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments
    1. Janine Kirstein*,1,,
    2. Daisuke Morito2,,
    3. Taichi Kakihana25,
    4. Munechika Sugihara2,
    5. Anita Minnen36,
    6. Mark S Hipp4,
    7. Carmen Nussbaum‐Krammer3,
    8. F Ulrich Hartl*,4,
    9. Kazuhiro Nagata*,2 and
    10. Richard I Morimoto*,3
    1. 1Leibniz‐Institute for Molecular Pharmacology (FMP) im Forschungsverbund Berlin, Berlin, Germany
    2. 2Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita‐ku, Kyoto, Japan
    3. 3Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA
    4. 4Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany
    5. 5Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
    6. 6Max Planck Institute of Biochemistry, Martinsried, Germany
    1. * Corresponding author. Tel: +49 3094793 250; E‐mail: kirstein{at}fmp-berlin.de

      Corresponding author. Tel: +49 8985782244; E‐mail: uhartl{at}biochem.mpg.de

      Corresponding author. Tel: +81 757053134; E‐mail: nagata{at}cc.kyoto-su.ac.jp

      Corresponding author. Tel: +1 8474913340; E‐mail: r-morimoto{at}northwestern.edu

    1. These authors contributed equally to this work

    Using genetically encoded sensors this study shows that the opposing redox state in ER lumen and cytosol is altered during ageing and upon disruption of proteostasis. The resulting redox imbalance can spread across tissues.

    Synopsis

    Using genetically encoded sensors this study shows that the opposing redox state in ER lumen and cytosol is altered during ageing and upon disruption of proteostasis. The resulting redox imbalance can spread across tissues.

    • Genetically encoded redox sensors report on tissue‐ and compartment‐specific redox state in C. elegans and HeLa cells.

    • Young animals have an oxidized ER that changes towards more reducing conditions during ageing, whereas the cytosol is reducing in young animals and becomes oxidizing with the progression of ageing.

    • Proteotoxic challenges such as the inhibition of the proteasome or protein aggregates provoke a similar response and also act in a trans‐compartmental manner.

    • The organellar redox homeostasis is regulated across tissues and responds to proteotoxic challenges in a distal tissue.

    • ageing
    • ER
    • proteostasis
    • redox homeostasis
    • Received April 5, 2015.
    • Revision received June 26, 2015.
    • Accepted July 2, 2015.
    Janine Kirstein, Daisuke Morito, Taichi Kakihana, Munechika Sugihara, Anita Minnen, Mark S Hipp, Carmen Nussbaum‐Krammer, F Ulrich Hartl, Kazuhiro Nagata, Richard I Morimoto
  • New friends for Ago2 in neuronal plasticity
    New friends for Ago2 in neuronal plasticity
    1. Farahnaz Sananbenesi1,2 and
    2. Andre Fischer (afische2{at}gwdg.de)1,3
    1. 1Research Group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
    2. 2DZNE RNAome Biology, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
    3. 3Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany

    MicroRNAs have emerged as central regulators of cellular homeostasis and increasing evidence suggests that they play a key role in neuronal plasticity. Major efforts are made to define microRNA networks and their targets in the brain. The mechanisms by which microRNA activity is regulated are, however, relatively unexplored. In this issue of The EMBO Journal, Störchel et al (2015) screened for proteins that affect microRNA function in neurons. They identify Nova1 and Ncoa3 as novel regulators of miRNA activity and demonstrate that both proteins are essential for neuronal plasticity in a microRNA‐dependent manner.

    See also: PH Störchel et al

    A screen for factors modulating miRNA function in neurons identifies two new regulators of Ago2 activity and shows these to be required for neuronal plasticity.

    Farahnaz Sananbenesi, Andre Fischer
  • Scissors for autolysosome tubules
    Scissors for autolysosome tubules
    1. Yang Chen1 and
    2. Li Yu (liyulab{at}mail.tsinghua.edu.cn)1
    1. 1The State Key Laboratory of Membrane Biology, Tsinghua University‐Peking University Joint Center for Life Sciences School of Life Sciences Tsinghua University, Beijing, China

    Autophagic lysosome reformation (ALR) is a cellular process in which lysosomes are reformed through scission of proto‐lysosomes from tubular structures extruded from autolysosomes. Despite recent progress, the molecular mechanism of ALR is far from clear. A paper in this issue of The EMBO Journal has identified lysosome‐localized PI(3)P, which is generated by the VPS34–UVRAG complex in an mTOR‐dependent manner, as an important regulator of autolysosome tubule scission (Munson et al, 2015).

    See also: MJ Munson et al

    At the end of the autophagic process, lysosomes need to reform via autophagic lysosome reformation. Phospholipid PI(3)P aids in this process downstream of mTOR and VPS34–UVRAG activity.

    Yang Chen, Li Yu
  • Huntington's disease—the sting in the tail
    Huntington's disease—the sting in the tail
    1. Maria Jimenez‐Sanchez1 and
    2. David C Rubinsztein (dcr1000{at}hermes.cam.ac.uk)1
    1. 1Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge School of Clinical Medicine, Cambridge, UK

    Huntington's disease (HD) is a progressive neurodegenerative condition caused by the abnormal expansion of a polyglutamine tract in the N‐terminus of the huntingtin protein. Over the last 20 years, HD pathogenesis has been explained by the generation of N‐terminal fragments containing the polyglutamine stretch. A new study from Frederic Saudou's group now investigates the function of the C‐terminal fragments generated upon cleavage and shows that these products may also contribute to cellular toxicity in HD (El‐Daher et al, 2015).

    See also: M‐T El‐Daher et al

    While it is well established that abnormal expansion of a polyQ tract in the huntingtin protein N‐terminus triggers Huntington's disease, recent findings show that C‐terminal cleavage fragments also contribute to cellular toxicity.

    Maria Jimenez‐Sanchez, David C Rubinsztein
  • Cell cycle‐dependent ubiquitylation and destruction of NDE1 by CDK5‐FBW7 regulates ciliary length
    Cell cycle‐dependent ubiquitylation and destruction of NDE1 by CDK5‐FBW7 regulates ciliary length
    1. Dipak Maskey1,
    2. Matthew Caleb Marlin2,
    3. Seokho Kim1,
    4. Sehyun Kim13,
    5. E‐Ching Ong1,
    6. Guangpu Li2 and
    7. Leonidas Tsiokas*,1
    1. 1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    2. 2Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    3. 3Laboratory of Pediatric Brain Disease, The Rockefeller University, New York, NY, USA
    1. *Corresponding author. Tel: +1 405 271 8001 ext. 46211; E‐mail: ltsiokas{at}ouhsc.edu

    Quiescence‐specific kinase CDK5 initiates NDE1 degradation to couple cell cycle state to length control of primary cilia.

    Synopsis

    Biogenesis and disassembly of primary cilia are coupled to the cell cycle by incompletely understood mechanisms. This study identifies such a link, by which a quiescence‐specific kinase controls the levels of a negative regulator of ciliary length.

    • Primary cilia are formed in quiescent cells.

    • NDE1, a negative regulator of ciliary length, is downregulated in quiescent cells.

    • CDK5, a kinase active in quiescent cells, phosphorylates NDE1 within an FBW7‐specific phosphodegron.

    • The FBW7 E3 ligase recognizes and targets phosphorylated NDE1 for degradation via the ubiquitin–proteasome system.

    • Destruction of NDE1 in G1/G0 allows cilia to reach their proper length.

    • CDK5
    • cilia
    • FBW7
    • NDE1
    • p35
    • Received December 17, 2014.
    • Revision received June 7, 2015.
    • Accepted June 29, 2015.
    Dipak Maskey, Matthew Caleb Marlin, Seokho Kim, Sehyun Kim, E‐Ching Ong, Guangpu Li, Leonidas Tsiokas
  • Triggered Ca2+ influx is required for extended synaptotagmin 1‐induced ER‐plasma membrane tethering
    <div xmlns="http://www.w3.org/1999/xhtml">Triggered Ca<sup>2+</sup> influx is required for extended synaptotagmin 1‐induced ER‐plasma membrane tethering</div>
    1. Olof Idevall‐Hagren*,1,2,3,4,
    2. Alice Lü2,3,4,
    3. Beichen Xie1 and
    4. Pietro De Camilli*,2,3,4
    1. 1Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
    2. 2Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
    3. 3Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
    4. 4Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA
    1. * Corresponding author. Tel: +46 18 471 4428; Fax: +46 18 471 4059; E‐mail: olof.idevall{at}mcb.uu.se

      Corresponding author. Tel: +1 203 737 4461; Fax: +1 203 737 4436; E‐mail: pietro.decamilli{at}yale.edu

    Following extracellular Ca2+ influx, extended‐synaptotagmins (E‐Syts) mediate ER‐plasma membrane tethering. Tethering requires the PI(4,5)P2‐binding C2‐domains of E‐Syt1 and and is regulated by E‐Syt2. E‐Syt1 plasma membrane binding resembles the one of synaptotagmin 1, the Ca2+‐sensor mediating exocytosis.

    Synopsis

    ER‐plasma membrane tethering mediated by the extended‐synaptotagmins (E‐Syts) requires extracellular Ca2+ influx, involves cooperation between Ca2+‐ and PI(4,5)P2‐binding C2‐domains within E‐Syt1 and is regulated by E‐Syt1 homodimerization and heterodimerization with E‐Syt2.

    • Recruitment of E‐Syt1 to ER‐plasma membrane contacts requires micromolar cytosolic Ca2+ concentrations and occurs physiologically after influx of extracellular Ca2+.

    • Cooperative actions between the Ca2+‐binding C2C domain and the PI(4,5)P2‐binding C2E domain of E‐Syt1 are required for its ER‐plasma membrane tethering function.

    • The C2‐domains of E‐Syt1 and of the Ca2+‐sensor for exocytosis, synaptotagmin 1, bind the plasma membrane with similar cytosolic Ca2+ dependence.

    • In pancreatic beta cells, Ca2+‐triggered insulin secretion and Ca2+‐induced E‐Syt1 mediated ER‐plasma membrane tethering occurs in parallel.

    • membrane contact sites
    • Orai1
    • PLC
    • STIM1
    • tricalbin
    • Received March 18, 2015.
    • Revision received June 22, 2015.
    • Accepted June 24, 2015.
    Olof Idevall‐Hagren, Alice , Beichen Xie, Pietro De Camilli