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  • DUBs counteract parkin for efficient mitophagy
    1. Ivan Dikic1 and
    2. Anja Bremm (bremm{at}em.uni-frankfurt.de) 1
    1. 1Institute of Biochemistry II and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany

    The Parkinson's disease‐associated ubiquitin E3 ligase parkin impacts various cellular processes including the autophagic clearance of defective mitochondria. In this issue of The EMBO Journal, Durcan et al (2014) reveal a novel control mechanism of parkin‐mediated mitophagy via the selective removal of atypical K6‐linked ubiquitin chains from parkin by the deubiquitinase USP8. Together with recent studies on USP15 and USP30, this establishes a functional role for deubiquitination in mitophagy regulation.

    See also: TM Durcan et al

    The Parkinson's disease‐associated ubiquitin ligase parkin is regulated by the deubiquitinases USP8, USP15 and USP30 — either directly through de‐ubiquitination of parkin or by removing ubiquitin from mitochondrial proteins, ensuring regulation of the ubiquitin signals that trigger mitophagy.

    Ivan Dikic, Anja Bremm
  • The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density
    1. Kit M Lee1,
    2. Renzo Danuser2,
    3. Jens V Stein2,
    4. Delyth Graham3,
    5. Robert JB Nibbs1 and
    6. Gerard J Graham*,1
    1. 1Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK
    2. 2Theodor Kocher Institute University of Bern, Bern, Switzerland
    3. 3Institute of Cardiovascular and Medical Sciences College of Medical, Veterinary and Life Sciences University of Glasgow, Glasgow, UK
    1. *Corresponding author. Tel: +44 141 330 3982; Fax: +44 141 330 4297; E‐mail: Gerard.graham{at}glasgow.ac.uk

    The chemokine CCL2 and its scavenging receptor ACKR2 antagonistically regulate lymphatic vessel density. This is the result of the developmental control of the proximity of pro‐lymphangiogenic macrophages to lymphatic vessels.

    Synopsis

    The chemokine CCL2 and its scavenging receptor ACKR2 antagonistically regulate lymphatic vessel density. This is the result of the developmental control of the proximity of pro‐lymphangiogenic macrophages to lymphatic vessels.

    • ACKR2 deficiency is associated with increased lymphatic vessel density

    • This phenotype is developmentally established

    • CCR2 deficiency is associated with reduced lymphatic vessel density

    • ACKR2 and CCR2 reciprocally regulate macrophage proximity to lymphatic surfaces

    • atypical receptors
    • chemokine
    • development
    • lymphatic
    • macrophage
    • Received May 7, 2014.
    • Revision received August 12, 2014.
    • Accepted August 27, 2014.

    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.

    Kit M Lee, Renzo Danuser, Jens V Stein, Delyth Graham, Robert JB Nibbs, Gerard J Graham
  • Crystal structure of a c‐di‐AMP riboswitch reveals an internally pseudo‐dimeric RNA
    1. Christopher P Jones1 and
    2. Adrian R Ferré‐D'Amaré*,1
    1. 1Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, Bethesda, MD, USA
    1. *Corresponding author. Tel: +1 301 496 4096; Fax: +1 301 451 5459; E‐mail: adrian.ferre{at}nih.gov

    C‐di‐AMP is a recently discovered second messenger in bacteria that is detected by both RNA and proteins. The crystal structure of ydaO, a c‐di‐AMP binding riboswitch, illustrates the basis for ligand specificity.

    Synopsis

    C‐di‐AMP is a recently discovered second messenger in bacteria that is detected by both RNA and proteins. The crystal structure of ydaO, a c‐di‐AMP binding riboswitch, illustrates the basis for ligand specificity.

    • The c‐di‐AMP riboswitch controls gene expression in a variety of bacteria.

    • The crystal structure reveals a symmetric RNA contacting two c‐di‐AMP molecules in similar ways.

    • The overall architecture of the riboswitch consists of two three‐helix subdomains that envelop the c‐di‐AMP ligands.

    • Ligand binding induces global folding of the riboswitch, the likely mechanism for control of gene expression.

    • cyclic di‐AMP
    • riboregulation
    • riboswitch
    • small‐angle X‐ray scattering
    • X‐ray crystallography
    • Received June 7, 2014.
    • Revision received August 25, 2014.
    • Accepted August 26, 2014.
    Christopher P Jones, Adrian R Ferré‐D'Amaré
  • Splicing together sister chromatids
    1. Juan Valcárcel1 and
    2. Marcos Malumbres (malumbres{at}cnio.es) 2
    1. 1Centre de Regulació Genòmica, Universitat Pompeu Fabra Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
    2. 2Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Splicing of pre‐mRNAs is a necessary step for expression of the majority of genes in higher eukaryotes, and its regulation through alternative splice site selection shapes their proteomes. Defects in multiple splicing factors result in aberrant mitotic progression, although the molecular basis for this observation has remained elusive. Recent papers in The EMBO Journal and EMBO Reports reveal that expression of sororin, a critical regulator that stabilizes cohesin rings in sister chromatids, is exquisitely sensitive to defects in the splicing machinery, thus explaining the striking link between spliceosome function and chromosome segregation.

    See also: S Sundaramoorthy et al,

    P van der Lelij et al,

    Y Oka et al and

    E Watrin et al

    Impaired spliceosome function triggers the loss of sister chromatid cohesion in interphase due a specific sensitivity of sororin to pre‐mRNA splicing.

    Juan Valcárcel, Marcos Malumbres
  • The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines
    1. Nikolaos Charlaftis1,,
    2. Tesha Suddason1,,
    3. Xuefeng Wu2,
    4. Saba Anwar1,
    5. Michael Karin2 and
    6. Ewen Gallagher*,1
    1. 1Department of Medicine, Imperial College London, London, UK
    2. 2Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, San Diego, CA, USA
    1. *Corresponding author. Tel: +44 20 3313 1782; E‐mail: ewen.gallagher{at}ntlworld.com
    1. These authors contributed equally to the work

    A RING domain‐like fold within the mouse MEK Kinase 1 polyubiquitylates TAK1‐binding protein 1 (TAB1), a critical adaptor in the TGF‐β signaling pathway, which stimulates Mitogen‐Activated Protein Kinase signaling and is required for correct embryonic stem cell differentiation and tumourigenicity, and for cardiac, testis and B‐cell development in mice in vivo.

    Synopsis

    The plant homeodomain (PHD) motif of mouse MEK Kinase 1 binds and polyubiquitylates TAK1‐binding protein 1 (TAB1). This is critical for potentiating EGF‐ and TGF‐β‐driven TAK1 and Mitogen‐Activated Protein Kinases activation for correct embryonic stem cell differentiation, and for cardiac, testis and B‐cell development in mice in vivo.

    • Protein array screening identifies the TAB1 adaptor protein, but not TAB2 or TAB3, as a substrate for the E3 ubiquitin ligase activity encoded in MEKK1's PHD motif.

    • The MEKK1 PHD motif ubiquitylates TAB1 with Lys63‐linked polyubiquitin to induce activation of the Transforming growth factor beta‐activated kinase 1 (TAK1) and of JNK and p38 MAP Kinases following Epidermal growth factor and Transforming growth factor‐beta stimulation. This is important for correct regulation of mouse embryonic stem cell differentiation and ES‐cell tumourigenicity.

    • In vivo, the MEKK1 PHD is essential for embryonic survival, and critically regulates mouse cardiac muscle, testis and B‐cell development, as well as T‐cell receptor signal transduction.

    • differentiation
    • signalling
    • stem cell
    • tumourigenesis
    • ubiquitin
    • Received February 27, 2014.
    • Revision received August 13, 2014.
    • Accepted August 22, 2014.

    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.

    Nikolaos Charlaftis, Tesha Suddason, Xuefeng Wu, Saba Anwar, Michael Karin, Ewen Gallagher
  • SNW1 enables sister chromatid cohesion by mediating the splicing of sororin and APC2 pre‐mRNAs
    1. Petra van der Lelij1,
    2. Roman R Stocsits1,
    3. Rene Ladurner1,
    4. Georg Petzold1,
    5. Emanuel Kreidl1,
    6. Birgit Koch1,2,
    7. Julia Schmitz13,
    8. Beate Neumann2,
    9. Jan Ellenberg2 and
    10. Jan‐Michael Peters*,1
    1. 1IMP Research Institute of Molecular Pathology, Vienna, Austria
    2. 2EMBL Heidelberg, Heidelberg, Germany
    3. 3Federal Joint Committee, Berlin, Germany
    1. *Corresponding author: Tel: +43 1797303002; E‐mail: Jan-Michael.Peters{at}imp.ac.at

    Loss of splicesome subunits SNW1 and PRPF8 leads to altered intron retention in a specific set of genes and depletes expression of cohesion loading factor sororin, explaining the mitotic defects caused by aberrant pre‐mRNA splicing.

    Synopsis

    Loss of splicesome subunits SNW1 and PRPF8 leads to altered intron retention in a specific set of genes and depletes expression of cohesion loading factor sororin, explaining the mitotic defects caused by aberrant pre‐mRNA splicing.

    • The spliceosome subunits SNW1 and PRPF8 are essential for sister chromatid cohesion.

    • The main function of SNW1 in sister chromatid cohesion is to enable the splicing of pre‐mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2.

    • Defects in APC2 pre‐mRNA splicing reduce APC/C activity and contribute to cohesion defects by causing “cohesion fatigue”.

    • Transcriptome‐wide analysis reveal that a subset of splicing reactions is particularly sensitive to depletion of SNW1 or PRPF8.

    • The identification of introns that are retained in SNW1‐ or PRPF8‐depleted cells may help to understand phenotypes and diseases associated with splicing defects.

    • cell cycle
    • mitosis
    • pre‐mRNA splicing
    • sister chromatid cohesion
    • Received February 11, 2014.
    • Revision received August 1, 2014.
    • Accepted August 12, 2014.
    Petra van der Lelij, Roman R Stocsits, Rene Ladurner, Georg Petzold, Emanuel Kreidl, Birgit Koch, Julia Schmitz, Beate Neumann, Jan Ellenberg, Jan‐Michael Peters
  • Functional genomics identifies a requirement of pre‐mRNA splicing factors for sister chromatid cohesion
    1. Sriramkumar Sundaramoorthy13,
    2. María Dolores Vázquez‐Novelle1,
    3. Sergey Lekomtsev14,
    4. Michael Howell2 and
    5. Mark Petronczki*,1
    1. 1Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms Hertfordshire, UK
    2. 2High‐throughput Screening Laboratory, Cancer Research UK London Research Institute, London, UK
    3. 3Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
    4. 4 Medical Research Council Laboratory of Molecular Cell Biology, University College London, London, UK
    1. *Corresponding author. Tel: +44 1707 625837; E‐mail: mark.petronczki{at}cancer.org.uk

    Correct splicing of cohesin‐loading factor sororin is required for sister chromatid cohesion during interphase. Mutations in a splicing factor essential for cohesion is implicated in chronic lymphocytic leukemia.

    Synopsis

    Correct splicing of cohesin‐loading factor sororin is required for sister chromatid cohesion during interphase. Mutations in a splicing factor essential for cohesion is implicated in chronic lymphocytic leukemia.

    • Functional genomics identifies a set of 26 spliceosome subunits that are required for sister chromatid cohesion in human cells.

    • Loss of splicing factors increases the turnover of cohesin complexes on chromatin and abrogates sister chromatid cohesion during interphase.

    • Compromising splicing reduces the steady‐state levels of sororin, a factor required for the stable association of cohesin with chromatin.

    • Increasing sororin protein level or removing the cohesin release factor WAPL restores cohesion in cells lacking splicing factors.

    • The key connections between sister chromatids in human cells are exquisitely sensitive to sororin dosage and to defects in pre‐mRNA splicing.

    • Recurrent splicing factor mutations in hyperproliferative haematological disorders may affect cohesin turnover on chromatin.

    • chromosome
    • cohesin
    • cohesion
    • mitosis
    • splicing
    • Received February 14, 2014.
    • Revision received August 3, 2014.
    • Accepted August 18, 2014.

    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.

    Sriramkumar Sundaramoorthy, María Dolores Vázquez‐Novelle, Sergey Lekomtsev, Michael Howell, Mark Petronczki