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  • MALT1 protease: equilibrating immunity versus tolerance
    1. Arianna Bertossi1 and
    2. Daniel Krappmann (daniel.krappmann{at}helmholtz-muenchen.de) 1
    1. 1Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany

    MALT1 paracaspase links signaling cascades emanating from adaptive or innate immune receptors to the canonical NF‐κB pathway. Now, Jaworski et al (2014) investigate the physiological role of MALT1 protease activity in mice. Besides the expected requirement of MALT1 activity for immune activation, the study unveils a novel function for MALT1 activity for the development of peripheral tolerance. Thus, MALT1 protease can act immunogenic or tolerogenic, and this interplay will be highly relevant for the clinical development of MALT1 inhibitors.

    See also: M Jaworski et al

    The unexpected finding that the NF‐κB‐regulating MALT1 protease can act either immunogenic or tolerogenic in vivo bears important implications for the clinical development of MALT1 inhibitors.

    Arianna Bertossi, Daniel Krappmann
  • Unfolded protein response‐induced ERdj3 secretion links ER stress to extracellular proteostasis
    1. Joseph C Genereux1,2,,
    2. Song Qu1,2,3,,
    3. Minghai Zhou4,
    4. Lisa M Ryno1,2,
    5. Shiyu Wang5,
    6. Matthew D Shoulders27,
    7. Randal J Kaufman5,
    8. Corinne I Lasmézas4,
    9. Jeffery W Kelly1,2,6 and
    10. R Luke Wiseman*,1,3
    1. 1Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
    2. 2Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
    3. 3Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA
    4. 4Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL, USA
    5. 5Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, CA, USA
    6. 6The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
    7. 7Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
    1. *Corresponding author. Tel: +1 858 784 8820; Fax: +1 858 784 8891; E‐mail: wiseman{at}scripps.edu
    1. These authors contributed equally to this work

    The unfolded protein response triggers secretion of ER chaperone ERdj3 to prevent formation of toxic aggregates, providing the first mechanistic link between intracellular stress signaling and extracellular proteostasis.

    Synopsis

    The unfolded protein response (UPR) triggers secretion of ER chaperone ERdj3 to prevent formation of toxic aSggregates, providing the first mechanistic link between intracellular stress signaling and extracellular proteostasis.

    • ERdj3 is an ER‐stress‐induced secreted chaperone

    • Secretion of ERdj3 is induced by the ATF6 arm of the UPR

    • Secretion of ERdj3 enhances extracellular proteostasis capacity

    • ERdj3 can co‐secrete as a stable complex with misfolding‐prone protein clients

    • ERdj3 serves as a link between intracellular and extracellular proteostasis capacity during ER stress.

    • ER stress
    • ERjd3
    • extracellular proteostasis
    • molecular chaperones
    • unfolded protein response
    • Received May 7, 2014.
    • Revision received September 9, 2014.
    • Accepted September 23, 2014.
    Joseph C Genereux, Song Qu, Minghai Zhou, Lisa M Ryno, Shiyu Wang, Matthew D Shoulders, Randal J Kaufman, Corinne I Lasmézas, Jeffery W Kelly, R Luke Wiseman
  • Shedding of glycan‐modifying enzymes by signal peptide peptidase‐like 3 (SPPL3) regulates cellular N‐glycosylation
    1. Matthias Voss1,
    2. Ulrike Künzel19,
    3. Fabian Higel2,
    4. Peer‐Hendrik Kuhn3,4,
    5. Alessio Colombo3,
    6. Akio Fukumori3,
    7. Martina Haug‐Kröper1,
    8. Bärbel Klier3,
    9. Gudula Grammer1,
    10. Andreas Seidl2,
    11. Bernd Schröder5,
    12. Reinhard Obst6,
    13. Harald Steiner1,3,
    14. Stefan F Lichtenthaler3,7,8,
    15. Christian Haass1,3,7 and
    16. Regina Fluhrer*,1,3
    1. 1Adolf Butenandt Institute for Biochemistry, Ludwig‐Maximilians University Munich, Munich, Germany
    2. 2Sandoz Biopharmaceuticals/HEXAL AG, Oberhaching, Germany
    3. 3DZNE – German Center for Neurodegenerative Diseases, Munich, Germany
    4. 4Institute for Advanced Study, Technische Universität München, Garching, Germany
    5. 5Biochemical Institute, Christian‐Albrechts‐University Kiel, Kiel, Germany
    6. 6Institute for Immunology, Ludwig‐Maximilians University Munich, Munich, Germany
    7. 7Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
    8. 8Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    9. 9Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
    1. *Corresponding author. Tel: +49 89 218075487; Fax: +49 89 218075415; E‐mail: rfluhrer{at}med.uni-muenchen.de

    The intramembrane‐cleaving GxGD‐type aspartyl protease, SPPL3, controls the proteolytic release of the ectodomain of glycosyltransferases and glycosidases to regulate cellular N‐glycosylation.

    Synopsis

    SPPL3 is a highly conserved eukaryotic intramembrane‐cleaving GxGD‐type aspartyl protease of undefined function. We show that SPPL3 liberates medial/trans‐Golgi glycosyltransferases from their N‐terminal membrane anchors to regulate the intracellular pool of active Golgi glycosyltransferases and the extent of N‐glycan decoration of cellular glycoproteins.

    • Loss of SPPL3 in vitro and in vivo is associated with more extensive N‐glycosylation.

    • Overexpression of active SPPL3, but not of an inactive mutant, leads to less extensive N‐glycosylation.

    • Constitutive secretion of Golgi glycosyltransferases such as GnT‐V, β3GnT1 and β4GalT1 is dependent on cellular SPPL3 activity.

    • SPPL3‐dependent GnT‐V endoproteolysis occurs close to GnT‐V's predicted transmembrane domain.

    • Changes in SPPL3 expression strongly affect intracellular glycosyltransferase levels, explaining the observed alterations in N‐glycan composition.

    • glycosyltransferases
    • GxGD aspartyl proteases
    • protein glycosylation
    • signal peptide peptidase like‐3
    • Received March 3, 2014.
    • Revision received September 19, 2014.
    • Accepted September 22, 2014.
    Matthias Voss, Ulrike Künzel, Fabian Higel, Peer‐Hendrik Kuhn, Alessio Colombo, Akio Fukumori, Martina Haug‐Kröper, Bärbel Klier, Gudula Grammer, Andreas Seidl, Bernd Schröder, Reinhard Obst, Harald Steiner, Stefan F Lichtenthaler, Christian Haass, Regina Fluhrer
  • APC/CCdh1 controls CtIP stability during the cell cycle and in response to DNA damage
    1. Lorenzo Lafranchi1,,
    2. Harmen R de Boer2,,
    3. Elisabeth GE de Vries2,
    4. Shao‐En Ong3,
    5. Alessandro A Sartori*,1 and
    6. Marcel ATM van Vugt*,2
    1. 1Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
    2. 2Department of Medical Oncology, University Medical Center Groningen University of Groningen, Groningen, The Netherlands
    3. 3Department of Pharmacology, University of Washington, Seattle, WA, USA
    1. * Corresponding author. Tel: +41 446353473; Fax: +41 446353484; E‐mail: sartori{at}imcr.uzh.ch

      Corresponding author. Tel: +31 50 3619554; Fax: +31 50 3614862; E‐mail: m.vugt{at}umcg.nl

    1. These authors contributed equally to this work

    Regulation of CtIP, a DNA‐end resection factor involved in repair pathway choice, represents a new means of genome stability control by the cell cycle ubiquitin ligase APC/C.

    Synopsis

    The master cell cycle ubiquitin ligase anaphase‐promoting complex/cyclosome (APC/C) and its Cdh1 cofactor play additional roles in ensuring genome stability. Regulation of the DNA‐end resection and repair pathway choice factor CtIP identifies a new means for APC/C control of DNA double‐strand break (DSB) repair.

    • Cdh1 depletion in human cells leads to increased genomic instability and enhanced sensitivity to DNA‐damaging agents.

    • A proteomic screen identifies CtIP as a novel APC/CCdh1 substrate.

    • A conserved KEN box degron in CtIP mediates Cdh1 binding and APC/C targeting.

    • Cdh1 promotes CtIP ubiquitination and proteasomal degradation after mitotic exit and in response to DNA damage.

    • Non‐degradable KEN box‐mutated CtIP persists at DSBs, leading to DSB hyper‐resection in G2 phase and defects in homologous recombination.

    • Cdh1
    • cell cycle
    • CtIP
    • DNA damage
    • DNA double‐strand break repair
    • Received May 16, 2014.
    • Revision received September 7, 2014.
    • Accepted September 30, 2014.
    Lorenzo Lafranchi, Harmen R de Boer, Elisabeth GE de Vries, Shao‐En Ong, Alessandro A Sartori, Marcel ATM van Vugt
  • Parkin‐independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain
    1. Yusuke Kageyama1,
    2. Masahiko Hoshijima2,,
    3. Kinya Seo3,,
    4. Djahida Bedja3,,
    5. Polina Sysa‐Shah4,,
    6. Shaida A Andrabi5,6,7,
    7. Weiran Chen6,
    8. Ahmet Höke6,
    9. Valina L Dawsn5,6,7,
    10. Ted M Dawson5,6,7,
    11. Kathleen Gabrielson4,
    12. David A Kass3,
    13. Miho Iijima1 and
    14. Hiromi Sesaki*,1
    1. 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    2. 2Center for Research in Biological Systems and Department of Medicine, University of California San Diego, La Jolla, CA, USA
    3. 3Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    4. 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    5. 5Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA
    6. 6Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    7. 7Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA
    1. *Corresponding author. Tel: +1 410 502 6842; E‐mail: hsesaki{at}jhmi.edu
    1. These authors contributed equally to this work

    In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.

    Synopsis

    In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease‐associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.

    • Mitochondria divide in cardiomyocytes.

    • Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy.

    • Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin.

    • Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1‐regulated mitophagy.

    • Simultaneous loss of Drp1 and parkin increases mitophagy defects.

    • mice
    • mitochondria
    • organelle division
    • respiration
    • Received April 16, 2014.
    • Revision received August 18, 2014.
    • Accepted September 19, 2014.
    Yusuke Kageyama, Masahiko Hoshijima, Kinya Seo, Djahida Bedja, Polina Sysa‐Shah, Shaida A Andrabi, Weiran Chen, Ahmet Höke, Valina L Dawsn, Ted M Dawson, Kathleen Gabrielson, David A Kass, Miho Iijima, Hiromi Sesaki
  • Structure of the Rad50 DNA double‐strand break repair protein in complex with DNA
    1. Anna Rojowska1,
    2. Katja Lammens1,
    3. Florian U Seifert1,
    4. Carolin Direnberger13,
    5. Heidi Feldmann1 and
    6. Karl‐Peter Hopfner*,1,2
    1. 1Department of Biochemistry and Gene Center, Ludwig‐Maximilians‐University, Munich, Germany
    2. 2Center for Integrated Protein Sciences, Munich, Germany
    3. 3SuppreMol GmbH, Munich, Germany
    1. *Corresponding author. Tel: +49 89 2180 76953; Fax: +49 89 2180 76999; E‐mail: hopfner{at}genzentrum.lmu.de

    The first structural insight into DNA binding by an SMC protein reveals the importance of Rad50–DNA interaction for some but not other functions of the MRN complex.

    Synopsis

    The SMC protein Rad50 is a key subunit of the MRN complex, a repair factor involved in processing and tethering DNA double‐strand breaks. First structural insights into its interaction with DNA show that such binding is important for some but not other functions of the MRN complex.

    • Thermotoga maritima Rad50 in complex with dsDNA offers the first crystal structure view of DNA binding by an SMC protein.

    • dsDNA binds to a strand‐loop‐helix motif on the Rad50 nucleotide‐binding domain.

    • DNA binds between the coiled‐coil domains of the ATP‐bound dimer of Rad50.

    • The strand‐loop‐helix motif does not directly recognize DNA ends, but rather binds a DNA duplex internally.

    • In yeast, DNA binding to the strand‐loop‐helix motif is important for MRN complex function in telomere maintenance but not in DNA double‐strand break repair.

    • crystal structure
    • DNA double‐strand break repair
    • homologous recombination
    • Mre11–Rad50
    • protein:DNA complex
    • Received May 5, 2014.
    • Revision received September 3, 2014.
    • Accepted September 25, 2014.
    Anna Rojowska, Katja Lammens, Florian U Seifert, Carolin Direnberger, Heidi Feldmann, Karl‐Peter Hopfner
  • How stem cells get “turned on”
    1. Amy J Wagers (amy_wagers{at}harvard.edu) 1
    1. 1Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA

    Recent research began to link autophagic processes to the functional integrity of certain stem cells. A novel study published in this issue of The EMBO Journal reports on autophagic flux as crucial checkpoint to meet the energy demands during muscle stem cell activation.

    See also: AH Tang & TA Rando

    Activation of muscle stem cells requires defined energy levels. Recent results determine autophagic flux as crucial contributor to the metabolic state of muscle stem cells.

    Amy J Wagers