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  • USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death
    USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death
    1. Jin‐Rui Liang1,
    2. Aitor Martinez1,2,3,
    3. Jon D Lane4,
    4. Ugo Mayor2,3,
    5. Michael J Clague*,1 and
    6. Sylvie Urbé*,1
    1. 1Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
    2. 2CIC Biogune Bizkaia Teknologi Parkea, Derio, Spain
    3. 3IKERBASQUE Basque Foundation for Science, Bilbao, Spain
    4. 4School of Biochemistry, University of Bristol, Bristol, UK
    1. * Corresponding author. Tel: +44 151 7945308; E‐mail: clague{at}liv.ac.uk

      Corresponding author. Tel: +44 151 7945432; E‐mail: urbe{at}liv.ac.uk

    USP30, recently described to counteract Parkin E3 ligase activity on mitochondria, is shown to regulate the mitochondrial pathway of apoptotic cell death in response to Parkin overexpression and the broadly used BH3‐mimetic therapeutic compounds.

    Synopsis

    USP30, recently described to counteract Parkin E3 ligase activity on mitochondria, is shown to regulate the mitochondrial pathway of apoptotic cell death in response to Parkin overexpression and the broadly used BH3‐mimetic therapeutic compounds.

    • hTERT‐RPE1‐cells stably overexpressing YFP‐Parkin undergo depolarisation‐induced, PINK1‐ and caspase‐dependent cell death, which is sensitive to proteasome but not lysosomal inhibitors.

    • USP30 depletion promotes Parkin‐dependent ubiquitylation of TOM20 and its subsequent degradation.

    • USP30 depletion enhances depolarization‐induced and Parkin‐dependent cell death.

    • Depletion of USP30 sensitizes RPE1, U2‐OS and MCF7 cells to BH3‐mimetics and promotes BAX/BAK‐dependent apoptotic cell death.

    • apoptosis
    • mitophagy
    • Parkin
    • TOM20
    • USP30
    • Received October 31, 2014.
    • Revision received February 10, 2015.
    • Accepted February 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.

    Jin‐Rui Liang, Aitor Martinez, Jon D Lane, Ugo Mayor, Michael J Clague, Sylvie Urbé
  • Effects of inflammation on stem cells: together they strive?
    Effects of inflammation on stem cells: together they strive?
    1. Caghan Kizil*,1,2,,
    2. Nikos Kyritsis2, and
    3. Michael Brand*,2
    1. 1German Centre for Neurodegenerative Diseases (DZNE) Dresden within the Helmholtz Association, Dresden, Germany
    2. 2DFG‐Center for Regenerative Therapies Dresden, Cluster of Excellence (CRTD) of the Technische Universität Dresden, Dresden, Germany
    1. * Corresponding author. Tel: +49 351 458 82315; E‐mail: caghan.kizil{at}dzne.de

      Corresponding author. Tel: +49 351 458 82300; E‐mail: michael.brand{at}biotec.tu-dresden.de

    1. These authors contributed equally to this work

    Inflammation is an important defense mechanism against pathogens or tissue damage, but it can also have detrimental consequences. This review focuses specifically on the effects of inflammation on stem cells.

    • disease
    • inflammation
    • neural stem cell
    • proliferation
    • regeneration
    • Received October 9, 2014.
    • Revision received February 19, 2015.
    • Accepted February 19, 2015.
    Caghan Kizil, Nikos Kyritsis, Michael Brand
  • WDFY1 mediates TLR3/4 signaling by recruiting TRIF
    WDFY1 mediates TLR3/4 signaling by recruiting TRIF
    1. Yun‐Hong Hu1,
    2. Yu Zhang1,
    3. Li‐Qun Jiang1,
    4. Shuai Wang1,
    5. Cao‐Qi Lei1,
    6. Ming‐Shun Sun1,
    7. Hong‐Bing Shu1 and
    8. Yu Liu*,1
    1. 1State Key Laboratory of Virology, Medical Research Institute College of Life Sciences Wuhan University, Wuhan, China
    1. *Corresponding author. Tel: +86 27 68753861; Fax: +86 27 68753780; E‐mail: yuliu{at}whu.edu.cn

    This study identifies a new important component of the TLR3/4 signaling pathway. Endosomal membrane protein WDFY1 interacts with both Toll‐like receptors upon ligand binding, and recruits the adaptor TRIF, enabling downstream signaling.

    Synopsis

    This study identifies a new important component of the TLR3/4 signaling pathway. Endosomal membrane protein WDFY1 interacts with both Toll‐like receptors and recruits the adaptor TRIF, enabling downstream signaling.

    • WDFY1 potentiates IRF3 and NF‐kB activation, as well as type I IFN and inflammatory cytokine production in response to poly(I:C) and LPS.

    • WDFY1 interacts with TLR3 and TLR4 in endosomal membranes of mouse macrophages upon stimulation, but not in resting cells.

    • WDFY1 recruits TRIF to TLR3 and TLR4 in a FYVE‐domain‐dependent manner.

    • signal transduction
    • TLR
    • TRIF
    • WDFY1
    • Received September 23, 2014.
    • Revision received February 7, 2015.
    • Accepted February 9, 2015.
    Yun‐Hong Hu, Yu Zhang, Li‐Qun Jiang, Shuai Wang, Cao‐Qi Lei, Ming‐Shun Sun, Hong‐Bing Shu, Yu Liu
  • Catching the adaptor—WDFY1, a new player in the TLR–TRIF pathway
    Catching the adaptor—WDFY1, a new player in the TLR–TRIF pathway
    1. Ramya Nandakumar1,2 and
    2. Søren R Paludan (srp{at}microbiology.au.dk) 1,2
    1. 1Department of Biomedicine, University of Aarhus, Aarhus, Denmark
    2. 2Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark

    The innate immune system detects microbes and abnormal self through pattern recognition receptors (PRRs), which detect molecules that are either specific for microbes (such as lipopolysaccharide), present in much higher concentrations during infection (such as double‐stranded RNA), or present in aberrant locations (such as cytosolic DNA) [1]. The Toll‐like receptors (TLRs) are the best‐described set of PRRs. TLRs are membrane‐bound receptors localized on the plasma membrane and in endosomes, the ligand‐binding regions of which face the extracellular environment and the endosomal lumen, respectively [1]. In this issue of EMBO Reports, Hu and colleagues report that WD‐repeat and FYVE‐domain‐containing protein 1 (WDFY1) recruits the signaling adaptor TRIF to TLR3 and TLR4, thereby potentiating signaling from these PRRs (Fig 1); [2].

    See also: Y‐H Hu et al

    WDFY1, an endosomal membrane protein, is a new crucial component of the TLR3/4 signaling pathway that enables the interaction of the adaptor TRIF with the TLRs after ligand binding.

    Ramya Nandakumar, Søren R Paludan
  • Potent degradation of neuronal miRNAs induced by highly complementary targets
    Potent degradation of neuronal miRNAs induced by highly complementary targets
    1. Manuel de la Mata1,
    2. Dimos Gaidatzis1,2,
    3. Mirela Vitanescu15,
    4. Michael B Stadler1,2,3,
    5. Corinna Wentzel46,
    6. Peter Scheiffele4,
    7. Witold Filipowicz*,1,3 and
    8. Helge Großhans*,1
    1. 1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    2. 2Swiss Institute of Bioinformatics, Basel, Switzerland
    3. 3University of Basel, Basel, Switzerland
    4. 4Biozentrum, University of Basel, Basel, Switzerland
    5. 5Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland
    6. 6Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    1. * Corresponding author. Tel: +41 61 697 6993; E‐mail: witold.filipowicz{at}fmi.ch

      Corresponding author. Tel: +41 61 697 6675; E‐mail: helge.grosshans{at}fmi.ch

    This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.

    Synopsis

    This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.

    • Target‐induced non‐templated nucleotide addition (tailing) occurs on miRNAs, while they are bound to Argonaute.

    • TDMD and mRNA silencing are independent processes, permitting one target to induce degradation of several miRNA molecules.

    • mRNA silencing, but not TDMD, requires cooperativity among multiple target sites to reach high efficiency.

    • cooperativity
    • miRNA target
    • miRNA turnover
    • non‐templated RNA 3′‐end nucleotide additions
    • primary hippocampal neurons
    • Received January 8, 2015.
    • Revision received January 21, 2015.
    • Accepted January 26, 2015.
    Manuel de la Mata, Dimos Gaidatzis, Mirela Vitanescu, Michael B Stadler, Corinna Wentzel, Peter Scheiffele, Witold Filipowicz, Helge Großhans
  • SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites
    SUMOylation and PARylation cooperate to recruit and stabilize SLX4 at DNA damage sites
    1. Román González‐Prieto*,1,
    2. Sabine AG Cuijpers1,
    3. Martijn S Luijsterburg2,
    4. Haico van Attikum2 and
    5. Alfred CO Vertegaal*,1
    1. 1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
    2. 2Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
    1. * Corresponding author. Tel: +31 71 5269621; E‐mail: Vertegaal{at}lumc.nl

      Corresponding author. Tel: +31 71 5269215; E‐mail: R.Gonzalez_Prieto{at}lumc.nl

    SLX4 is crucial for the repair of DNA interstrand crosslinks and maintaining genome stability. This study shows that its recruitment to damaged DNA depends on interaction with SUMO and subsequent SUMOylation, as well as on PARylation.

    Synopsis

    SLX4 is crucial for the repair of DNA interstrand crosslinks and maintaining genome stability. This study shows that its recruitment to damaged DNA depends on interaction with SUMO and subsequent SUMOylation, as well as on PARylation.

    • SLX4 is regulated by SUMO‐Interaction Motifs (SIMs).

    • SLX4 SUMOylation occurs during S‐ and G2‐phase of the cell cycle.

    • Mutating the SIMs in SLX4 reduces its accumulation at local sites of DNA damage.

    • SUMOylation enhances SLX4‐mediated resistance to mitomycin C in mouse cells.

    • DNA repair
    • PARP
    • SLX4
    • SUMO
    • ubiquitin
    • Received December 17, 2014.
    • Revision received February 6, 2015.
    • Accepted February 9, 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.

    Román González‐Prieto, Sabine AG Cuijpers, Martijn S Luijsterburg, Haico van Attikum, Alfred CO Vertegaal
  • The biology of IQGAP proteins: beyond the cytoskeleton
    The biology of IQGAP proteins: beyond the cytoskeleton
    1. Andrew C Hedman1,,
    2. Jessica M Smith1, and
    3. David B Sacks*,1
    1. 1Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, USA
    1. *Corresponding author. Tel: +1 301 496 3386; E‐mail: sacksdb{at}mail.nih.gov
    1. These authors contributed equally to this work

    IQGAP proteins regulate diverse cellular processes, including cytokinesis, migration, proliferation, and vesicle trafficking. This review discusses the roles of IQGAP proteins at the organismal level.

    • biology
    • IQGAP1
    • IQGAP2
    • IQGAP3
    • therapeutics
    • Received November 6, 2014.
    • Revision received December 22, 2014.
    • Accepted January 7, 2015.
    Andrew C Hedman, Jessica M Smith, David B Sacks