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  • Expression of Ca2+‐permeable two‐pore channels rescues NAADP signalling in TPC‐deficient cells
    <div xmlns="http://www.w3.org/1999/xhtml">Expression of Ca<sup>2+</sup>‐permeable two‐pore channels rescues NAADP signalling in TPC‐deficient cells</div>
    1. Margarida Ruas1,,
    2. Lianne C Davis1,,
    3. Cheng‐Chang Chen2,
    4. Anthony J Morgan1,
    5. Kai‐Ting Chuang14,
    6. Timothy F Walseth3,
    7. Christian Grimm2,
    8. Clive Garnham1,
    9. Trevor Powell1,
    10. Nick Platt1,
    11. Frances M Platt1,
    12. Martin Biel2,
    13. Christian Wahl‐Schott2,
    14. John Parrington*,1 and
    15. Antony Galione*,1
    1. 1Department of Pharmacology, University of Oxford, Oxford, UK
    2. 2Center for Integrated Protein Science CIPS‐M and Department of Pharmacy – Center for Drug Research, Ludwig‐Maximilians‐Universität München, München, Germany
    3. 3Pharmacology Department, University of Minnesota, Minneapolis, MN, USA
    4. 4The Center for Immunology and Inflammatory Diseases, Harvard Medical School, Boston, MA, USA
    1. * Corresponding author. Tel: +44 1865 271591; Fax: +44 1865 271853; E‐mail: john.parrington{at}pharm.ox.ac.uk

      Corresponding author. Tel: +44 1865 271633; Fax: +44 1865 271853; E‐mail: antony.galione{at}pharm.ox.ac.uk

    1. These authors contributed equally to this work

    By presenting a new double‐knockout mouse model this study demonstrates that two‐pore channels (TPCs) are responsible for NAADP‐dependent Ca2+ release from endo‐lysosomes.

    Synopsis

    By presenting a new double‐knockout mouse model this study demonstrates that two‐pore channels (TPCs) are responsible for NAADP‐dependent Ca2+ release from endo‐lysosomes.

    • Endogenous two‐pore channels (TPCs) are essential for NAADP‐stimulated Ca2+ currents and Ca2+ release.

    • Re‐expression of TPCs in validated null‐background cells restores NAADP sensitivity.

    • Truncated TPC1 and TPC2 proteins—potentially expressed in other reported TPC knockouts—are still functional.

    • TPCs are not required for high‐affinity NAADP‐binding.

    • PI(3,5)P2 is a promiscuous modulator of endo‐lysosomal channels.

    • Ca2+
    • electrophysiology
    • endo‐lysosome
    • NAADP
    • TPC
    • Received September 10, 2014.
    • Revision received March 6, 2015.
    • Accepted March 11, 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.

    Margarida Ruas, Lianne C Davis, Cheng‐Chang Chen, Anthony J Morgan, Kai‐Ting Chuang, Timothy F Walseth, Christian Grimm, Clive Garnham, Trevor Powell, Nick Platt, Frances M Platt, Martin Biel, Christian Wahl‐Schott, John Parrington, Antony Galione
  • Tregs strip dendritic cells of CD70 to regulate Th1 differentiation
    Tregs strip dendritic cells of CD70 to regulate Th1 differentiation
    1. Lukasz Wojciech1 and
    2. Leszek Ignatowicz (lignatowicz{at}gru.edu) 1
    1. 1Department of Medicine, Center for Biotechnology and Genomic Medicine Georgia Regents University, Augusta, GA, USA

    When the immune system encounters an antigen, the response can result in the mobilization of effector cells or in tolerance. The outcome is largely dependent on immunosuppressive CD4 T cells that express the transcription factor Foxp3 (Tregs). Yet, how Tregs control different immune effector cells remains elusive. In this issue of The EMBO Journal, Dhainaut et al report on a novel mechanism used by Tregs to prevent differentiation of naïve CD4 T cells to proinflammatory Th1CD4 (Th1) effectors.

    See also: M Dhainaut et al

    A recent study reveals a new mechanism by which regulatory T cells suppress excessive inflammatory responses.

    Lukasz Wojciech, Leszek Ignatowicz
  • Gut stem cells, a story of snails, flies and mice
    Gut stem cells, a story of snails, flies and mice
    1. Marc Amoyel (marc.amoyel{at}nyumc.org) 1
    1. 1Department of Biochemistry and Molecular Pharmacology, The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York, NY, USA

    Intestinal stem cells (ISCs) replenish and regenerate several types of cells in the gut, both during normal homeostasis and in response to various insults such as infections. Although gut structure and complexity vary across phyla, two functional categories of differentiated cell types are always present: absorptive cells and those of the secretory lineage. A series of studies in Drosophila and mouse published in The EMBO Journal, including one in this issue, identifies conserved roles for the Snail family of zinc finger transcription factors in regulating self‐renewal and differentiation of ISCs (Korzelius et al, 2014; Loza‐Coll et al, 2014; Horvay et al, 2015).

    See also: K Horvay et al,

    J Korzelius et al (December 2014) and

    MA Loza-Coll et al (December 2014)

    Functional work in various animal models establishes the Snail‐family transcription factor Escargot/Snai1 at the crossroad of intestinal stem cell self‐renewal and differentiation.

    Marc Amoyel
  • Ubiquitin‐like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway
    Ubiquitin‐like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway
    1. Yasuyoshi Oka1,
    2. Simon Bekker‐Jensen*,1 and
    3. Niels Mailand*,1
    1. 1Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    1. * Corresponding author. Tel: +45 35 32 50 24; Fax: +45 35 32 50 01; E‐mail: simon.bekker-jensen{at}cpr.ku.dk

      Corresponding author. Tel: +45 35 32 50 23; Fax: +45 35 32 50 01; E‐mail: niels.mailand{at}cpr.ku.dk

    An atypical ubiquitin‐like protein functions in DNA interstrand crosslink repair by impinging on FANCI–FANCD2 complex formation independent of its spliceosome‐modulating role.

    Synopsis

    UBL5/Hub1, a modulator of spliceosome function, is an atypical ubiquitin‐like protein that does not covalently modify other proteins. Interaction with Fanconi anemia (FA) pathway components reveals a new UBL5 role in DNA interstrand crosslink repair.

    • UBL5 promotes FA pathway functionality through pre‐mRNA‐splicing‐dependent and pre‐mRNA‐splicing‐independent mechanisms.

    • UBL5 directly binds to and stabilizes the central FA pathway component FANCI.

    • UBL5 facilitates FANCI–FANCD2 complex formation and function in cells.

    • FANCI forms homo‐oligomeric complexes dependent on its interaction with UBL5.

    • DNA damage response
    • FANCI
    • Fanconi anemia
    • protein stability
    • UBL5
    • Received October 22, 2014.
    • Revision received February 23, 2015.
    • Accepted March 19, 2015.
    Yasuyoshi Oka, Simon Bekker‐Jensen, Niels Mailand
  • A grab to move on: ER–endosome contacts in membrane protrusion formation and neurite outgrowth
    A grab to move on: ER–endosome contacts in membrane protrusion formation and neurite outgrowth
    1. Michael Krauß (krauss{at}fmp-berlin.de)1 and
    2. Volker Haucke (haucke{at}fmp-berlin.de) 1,2
    1. 1Leibniz Institut für Molekulare Pharmakologie (FMP) & Freie Universität Berlin, Berlin, Germany
    2. 2Neurocure Cluster of Excellence, Freie Universität & Charité Universitätsmedizin Berlin CCO, Berlin, Germany

    A key feature of many eukaryotic cells, most prominently seen in developing neurons, is their ability to form and extend membrane protrusions. How protrusion formation is linked to exocytic membrane trafficking is largely unclear. In a recent paper published in Nature, Raiborg et al identify a crucial role in this process for dynamic membrane contact sites (MCSs) between the ER and endosomes. The MCSs are formed by endoplasmic reticulum (ER)‐localized protein protrudin and the late endosomal kinesin adaptor FYCO1 and the small GTPase Rab7.

    See also: C Raiborg et al

    ER‐localized protrudin and phosphatidylinositol 3‐phosphate and Rab7 GTPase on late endosomes establish contact sites, to transfer kinesin‐1 to the motor adaptor FYCO1, allowing for the movement of late endosomes and thus outgrowth of protrusions and neurites.

    Michael Krauß, Volker Haucke
  • Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β‐cell function
    Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic β‐cell function
    1. Shiqi Jia*,1,,
    2. Andranik Ivanov2,,
    3. Dinko Blasevic1,
    4. Thomas Müller1,
    5. Bettina Purfürst3,
    6. Wei Sun46,
    7. Wei Chen4,
    8. Matthew N Poy5,
    9. Nikolaus Rajewsky2 and
    10. Carmen Birchmeier*,1
    1. 1Developmental Biology, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    2. 2Systems Biology of Gene Regulatory Elements, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    3. 3Electron Microscopy Platform, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    4. 4Scientific Genomics Platform, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    5. 5Molecular Mechanisms of Metabolic Disease, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany
    6. 6Department of Medical Oncology, Jiangsu Provincial Hospital of TCM, Nanjing, China
    1. * Corresponding author. Tel: +49 30 9406 2403; Fax: +49 30 9406 3765; E‐mail: cbirch{at}mdc-berlin.de

      Corresponding author. Tel: +49 30 9406 3848; Fax: +49 30 9406 3765; E‐mail: jshiqi{at}mdc-berlin.de

    1. These authors contributed equally to this work

    The functional and molecular characterization of Insm1 reveals its crucial role in the maintenance of adult pancreatic β‐cell identity.

    Synopsis

    The functional and molecular characterization of Insm1 reveals its crucial role in the maintenance of adult pancreatic β‐cell identity.

    • Deletion of Insm1 in adult pancreatic β‐cells in mice translates into deficits of insulin secretion.

    • Insm1/Neurod1/Foxa2 co‐occupy regulatory sequences to maintain a mature gene expression profile in pancreatic β‐cells.

    • Corresponding human Insm1/Neurod1/Foxa2 binding regions show sequence variations that have been implicated in β‐cell dysfunction(s).

    • development
    • differentiation
    • Insm1
    • maturation
    • metabolisms
    • pancreatic beta cells
    • Received December 16, 2014.
    • Revision received February 26, 2015.
    • Accepted March 10, 2015.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Shiqi Jia, Andranik Ivanov, Dinko Blasevic, Thomas Müller, Bettina Purfürst, Wei Sun, Wei Chen, Matthew N Poy, Nikolaus Rajewsky, Carmen Birchmeier
  • Blocking integrin inactivation as an anti‐angiogenic therapy
    Blocking integrin inactivation as an anti‐angiogenic therapy
    1. Pipsa Saharinen1 and
    2. Johanna Ivaska (joivaska{at}utu.fi) 2
    1. 1Wihuri Research Institute and Research Programs Unit, Translational Cancer Biology Program and Department of Virology, University of Helsinki, Helsinki, Finland
    2. 2Department of Food and Biochemistry, Turku Centre for Biotechnology University of Turku, Turku, Finland

    During angiogenesis, endothelial cell migration is coordinated by integrin‐mediated contact with the extra‐cellular matrix (ECM), coupled with receptor tyrosine kinase signalling to regulate dynamic cytoskeletal and plasma membrane reorganization. A recent paper by Vitorino et al (2015) defined a new MAP4K4–moesin–talin–β1‐integrin pathway that could be therapeutically exploited to suppress pathologic angiogenesis.

    See also: P Vitorino et al (March 2015)

    A recent study in Nature reports on the discovery of a MAP4K4‐dependent mechanism for integrin inactivation and endothelial cell migration. This leads the authors to pharmacological exploration for anti‐angiogenic therapies.

    Pipsa Saharinen, Johanna Ivaska