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  • Crosstalk between Akt/GSK3β signaling and dynamin‐1 regulates clathrin‐mediated endocytosis
    Crosstalk between Akt/GSK3β signaling and dynamin‐1 regulates clathrin‐mediated endocytosis
    1. Carlos R Reis1,,
    2. Ping‐Hung Chen1,,
    3. Saipraveen Srinivasan1,
    4. François Aguet2,
    5. Marcel Mettlen1 and
    6. Sandra L Schmid*,1
    1. 1Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA
    2. 2Department of Cell Biology, Harvard Medical School, Boston, MA, USA
    1. *Corresponding author. Tel: +1 214 648 3948; E‐mail: Sandra.Schmid{at}utsouthwestern.edu
    1. These authors contributed equally to this work

    Activation of dynamin‐1 by Akt and GSK3β in non‐neuronal cells alters the rate and regulation of CME, providing a feed‐forward pathway between signaling and endocytosis.

    Synopsis

    Dynamin‐1, previously thought to be neuron specific, is activated by an Akt/GSK3β signaling cascade in non‐neuronal cells. Dynamin‐1 activation alters the rate and regulation of clathrin‐mediated endocytosis, providing a feed‐forward pathway between endocytosis and signaling.

    • An endocytic checkpoint monitors the fidelity of clathrin‐coated vesicle (CCV) formation.

    • Dysregulated clathrin‐mediated endocytosis (CME) alters cell signaling and proliferation.

    • Dynamin‐1 and dynamin‐2 differentially regulate early stages of CME.

    • Endogenous dynamin‐1 is activated by an Akt/GSK3β signaling cascade, illustrating a first non‐neuronal role of dynamin‐1.

    • CME
    • endosomal trafficking
    • signaling
    • dynamin
    • CCP maturation
    • Received March 13, 2015.
    • Revision received May 26, 2015.
    • Accepted June 10, 2015.
    Carlos R Reis, Ping‐Hung Chen, Saipraveen Srinivasan, François Aguet, Marcel Mettlen, Sandra L Schmid
  • Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion
    <div xmlns="http://www.w3.org/1999/xhtml">Molecular profiling of CD8 T cells in autochthonous melanoma identifies <em>Maf</em> as driver of exhaustion</div>
    1. Marilyn Giordano1,2,3,
    2. Coralie Henin1,2,3,
    3. Julien Maurizio1,2,3,
    4. Claire Imbratta4,
    5. Pierre Bourdely1,2,3,
    6. Michel Buferne1,2,3,
    7. Lukas Baitsch4,
    8. Laurent Vanhille1,2,3,
    9. Michael H Sieweke1,2,3,5,
    10. Daniel E Speiser4,
    11. Nathalie Auphan‐Anezin1,2,3,
    12. Anne‐Marie Schmitt‐Verhulst1,2,3 and
    13. Grégory Verdeil*,1,2,36
    1. 1Centre d'Immunologie de Marseille‐Luminy (CIML), UM2 Aix‐Marseille Université, Marseille Cedex 9, France
    2. 2INSERM U1104, Marseille, France
    3. 3CNRS UMR7280, Marseille, France
    4. 4Clinical Tumor Biology & Immunotherapy Group, Department of Oncology and Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland
    5. 5Max‐Delbrück‐Centrum für Molekulare Medizin (MDC), Berlin, Germany
    6. 6Clinical Tumor Biology & Immunotherapy Group, Department of Oncology and Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland
    1. *Corresponding author. Tel: +41 21 692 5922; E‐mail: gregory.verdeil{at}unil.ch

    Transcriptome profiling of murine CD8 T cells from tumor tissue shows that the transcriptional regulator Maf1 is overexpressed in exhausted CD8 T cells and contributes to the dampening of anti‐tumor T‐cell responses.

    Synopsis

    Transcriptome profiling of murine CD8 T cells from tumor tissue shows that the transcriptional regulator Maf1 is overexpressed in exhausted CD8 T cells and contributes to the dampening of anti‐tumor T‐cell responses.

    • The transcriptomic profile of CD8 tumor‐infiltrated lymphocytes (TILs) from mouse melanoma shows strong similarities with the transcriptomic profile of CD8 T cells exhausted by chronic viral exposure.

    • The transcription factor Maf is overexpressed in mouse and human CD8 TILs from melanoma.

    • Overexpression of Maf in tumor‐specific CD8 T cells induces functional exhaustion of CD8 T cells and prevents anti‐tumor responses by them.

    • Antigen stimulation of CD8 T cells in the presence of TGFβ and/or IL‐6 induces Maf expression in those CD8 T cells.

    • Maf‐deficient tumor‐specific CD8 T cells have increased capacity to eliminate tumor cells in vivo.

    • Maf
    • melanoma
    • T‐cell exhaustion
    • TGFβ
    • Received December 12, 2014.
    • Revision received June 2, 2015.
    • Accepted June 8, 2015.
    Marilyn Giordano, Coralie Henin, Julien Maurizio, Claire Imbratta, Pierre Bourdely, Michel Buferne, Lukas Baitsch, Laurent Vanhille, Michael H Sieweke, Daniel E Speiser, Nathalie Auphan‐Anezin, Anne‐Marie Schmitt‐Verhulst, Grégory Verdeil
  • Myc or no Myc, that is the question
    Myc or no Myc, that is the question
    1. Chun Chou1 and
    2. Takeshi Egawa (tegawa{at}wustl.edu)1
    1. 1Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA

    The transcription factor c‐MYC functions as the master transcription factor for establishing highly active metabolic states in proliferating cells. c‐Myc is essential for rapid proliferation of normal cells and has causal relationship with many cancers, including leukemia and lymphoma. While the expression of c‐MYC can be aberrantly driven by genetic abnormalities, such as chromosomal translocations directly involving the MYC locus or mutations of its upstream regulators, how c‐MYC expression is induced and amplified in normal lymphocytes in response to antigen stimulation remains elusive. In this issue of The EMBO Journal, Preston et al (2015) report how c‐MYC is selectively induced and amplified in the antigen‐specific T cells that undergo massive clonal expansion for host protection against pathogen infection.

    See also: GC Preston et al

    Recent work illustrates how c‐MYC is selectively induced and amplified in antigen‐specific T cells that undergo massive clonal expansion for host protection against pathogen infection.

    Chun Chou, Takeshi Egawa
  • mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival
    mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival
    1. Michael J Munson1,
    2. George FG Allen1,
    3. Rachel Toth1,
    4. David G Campbell1,
    5. John M Lucocq2 and
    6. Ian G Ganley*,1
    1. 1MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences University of Dundee, Dundee, UK
    2. 2School of Medicine University of St Andrews, St Andrews, UK
    1. *Corresponding author. Tel: +44 1382 388905; E‐mail: i.ganley{at}dundee.ac.uk

    During starvation, VPS34 activity at the lysosomes controls autophagosome‐lysosome reformation and cell viability, illustrating a novel role for this autophagy‐initiating lipid kinase at late stages of autophagy.

    Synopsis

    During starvation, VPS34 activity at the lysosomes controls autophagosome‐lysosome reformation and cell viability, illustrating a novel role for this autophagy‐initiating lipid kinase at late stages of autophagy.

    • A small pool of phosphatidylinositol 3‐phosphate is present on lysosomes.

    • Pharmacological inhibition of VPS34 with low doses of VPS34‐IN1 results in increased autolysosomal tubulation.

    • mTOR directly phosphorylates UVRAG at serine 550 and serine 571 to activate VPS34.

    • Loss of mTOR phosphorylation sites on UVRAG leads to increased lysosomal tubulation and cell death upon prolonged starvation.

    • lysosome
    • mTOR
    • tubule
    • UVRAG
    • VPS34
    • Received January 11, 2015.
    • Revision received May 16, 2015.
    • Accepted June 4, 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.

    Michael J Munson, George FG Allen, Rachel Toth, David G Campbell, John M Lucocq, Ian G Ganley
  • Single cell tuning of Myc expression by antigen receptor signal strength and interleukin‐2 in T lymphocytes
    Single cell tuning of Myc expression by antigen receptor signal strength and interleukin‐2 in T lymphocytes
    1. Gavin C Preston1,
    2. Linda V Sinclair1,
    3. Aneesa Kaskar1,2,
    4. Jens L Hukelmann1,2,
    5. Maria N Navarro1,3,
    6. Isabel Ferrero4,
    7. H Robson MacDonald4,
    8. Victoria H Cowling2 and
    9. Doreen A Cantrell*,1
    1. 1Department of Cell Signalling & Immunology, College of Life Sciences University of Dundee, Dundee, UK
    2. 2Centre for Gene Regulation and Expression, College of Life Sciences University of Dundee, Dundee, UK
    3. 3Instituto Investigación Sanitaria/Hospital Universitario de la Princesa Universidad Autónoma de Madrid, Madrid, Spain
    4. 4Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, Switzerland
    1. *Corresponding author. Tel: +44 1382 385156; E‐mail: d.a.cantrell{at}dundee.ac.uk

    A combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during T lymphocyte immune responses and matches Myc expression to biosynthetic demands.

    Synopsis

    A combination of digital and analogue processes allows tight control of Myc expression at the population and single cell level during T lymphocyte immune responses and matches Myc expression to biosynthetic demands.

    • The T cell antigen receptor operates an essential on/off switch for Myc expression. The strength of the antigen stimulus determines the frequency of immune‐activated T cells that express Myc.

    • Myc protein has a very short half‐life in activated T cells because it is constantly phosphorylated by glycogen synthase kinase 3 (GSK3) and targeted for proteasomal degradation.

    • The constant high level of Myc proteolysis means Myc protein levels can only be sustained in T cells that have high rates of amino acid uptake and protein synthesis.

    • The post‐transcriptional control of Myc protein is used by pro‐inflammatory cytokines such as interleukin‐2 to fine‐tune Myc levels in individual T cells.

    • The fine‐tuning of Myc levels in individual T cells is shown to be important for a key aspect of T cell metabolism: the regulated uptake of transferrin that ensures immune‐activated T cells have sufficient iron.

    • cytokine signals
    • metabolism
    • Myc
    • T lymphocytes
    • TCR signals
    • Received October 7, 2014.
    • Revision received May 15, 2015.
    • Accepted May 18, 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.

    Gavin C Preston, Linda V Sinclair, Aneesa Kaskar, Jens L Hukelmann, Maria N Navarro, Isabel Ferrero, H Robson MacDonald, Victoria H Cowling, Doreen A Cantrell
  • The wound inflammatory response exacerbates growth of pre‐neoplastic cells and progression to cancer
    The wound inflammatory response exacerbates growth of pre‐neoplastic cells and progression to cancer
    1. Nicole Antonio1,,
    2. Marie Louise Bønnelykke‐Behrndtz2,3,,
    3. Laura Chloe Ward4,,
    4. John Collin4,
    5. Ib Jarle Christensen5,
    6. Torben Steiniche6,7,
    7. Henrik Schmidt*,7,8,
    8. Yi Feng*,9 and
    9. Paul Martin*,1,4,10
    1. 1School of Biochemistry, University of Bristol, Bristol, UK
    2. 2Department of Experimental Clinical Oncology, Aarhus University, Aarhus, Denmark
    3. 3Department of Plastic and Reconstructive Surgery, Aarhus University, Aarhus, Denmark
    4. 4School of Physiology and Pharmacology, University of Bristol, Bristol, UK
    5. 5Department of Public Health, University of Copenhagen, Copenhagen, Denmark
    6. 6Department of Pathology, Aarhus University, Aarhus, Denmark
    7. 7Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
    8. 8Department of Oncology, Aarhus University, Aarhus, Denmark
    9. 9MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
    10. 10School of Medicine, University of Cardiff, Cardiff, UK
    1. * Corresponding author. Tel: +45 7846 1682; E‐mail: henrschm{at}rm.dk

      Corresponding author. Tel: +44 131 242 6685; E‐mail: yi.feng{at}ed.ac.uk

      Corresponding author. Tel: +44 117 331 2298; E‐mail: paul.martin{at}bristol.ac.uk

    1. These authors contributed equally to this work

    Innate immune cells that are initially drawn to a wound can subsequently be attracted away to nearby cancer cells and drive their proliferation.

    Synopsis

    This study reveals how innate immune cells, in particular neutrophils, that are initially drawn to a wound can subsequently be attracted away to nearby early‐ and late‐stage cancer cells and drive their proliferation.

    • Both chronic and acute wounds exacerbate cancer growth.

    • Tissue damage in larval zebrafish, or cancer surgery in adults, draws in neutrophils and macrophages.

    • Neutrophils are recruited from wounds to nearby pre‐neoplastic cells and deliver trophic signals.

    • Neutrophil presence correlates with tumour cell proliferative index and indicates poor prognosis in ulcerated human melanoma.

    • cancer inflammation
    • cancer surgery
    • live imaging
    • melanoma
    • wound healing
    • Received September 30, 2014.
    • Revision received April 15, 2015.
    • Accepted May 25, 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.

    Nicole Antonio, Marie Louise Bønnelykke‐Behrndtz, Laura Chloe Ward, John Collin, Ib Jarle Christensen, Torben Steiniche, Henrik Schmidt, Yi Feng, Paul Martin
  • Membrane protrusion powers clathrin‐independent endocytosis of interleukin‐2 receptor
    Membrane protrusion powers clathrin‐independent endocytosis of interleukin‐2 receptor
    1. Cyril Basquin1,27,
    2. Michaël Trichet3,,
    3. Helena Vihinen4,,
    4. Valérie Malardé1,28,
    5. Thibault Lagache2,5,,
    6. Léa Ripoll1,29,
    7. Eija Jokitalo4,
    8. Jean‐Christophe Olivo‐Marin2,5,
    9. Alexis Gautreau6 and
    10. Nathalie Sauvonnet*,1,28
    1. 1Unité de Biologie des Interactions Cellulaires, Institut Pasteur, Paris, France
    2. 2CNRS UMR3691, Paris, France
    3. 3Sorbonne Universités, UPMC Univ Paris 06, CNRS, Institut de Biologie Paris‐Seine (IBPS), FR3631, Electron Microscopy Facility, Paris, France
    4. 4Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
    5. 5Unité d'Analyse d'Images Biologiques, Institut Pasteur, Paris, France
    6. 6Laboratoire de Biochimie, Unité Mixte de Recherche 7654 Ecole Polytechnique Centre, National de la Recherche Scientifique, Palaiseau, France
    7. 7Institut Jacques Monod, Equipe de Polarité Cellulaire dans le Développement et l'évolution, CNRS, UMR 7592, Paris, France
    8. 8 Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France
    9. 9 Institut Curie, and Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, Paris, France
    1. *Corresponding author. Tel: +33 145688433; E‐mail: nathalie.sauvonnet{at}pasteur.fr
    1. These authors contributed equally to this work

    The initiation of interleukin‐2 receptor (IL‐2R) endocytosis follows a unique mechanism of outward membrane deformation via protrusions and requires IL‐2R interaction with the WAVE complex.

    Synopsis

    The initiation of interleukin‐2 receptor (IL‐2R) endocytosis follows a unique mechanism of outward membrane deformation via protrusions and requires IL‐2R interaction with the WAVE complex.

    • Ultrastructural data demonstrate the presence of IL‐2R‐containing pits at the base of membrane protrusions.

    • The F‐actin activating WAVE complex interacts with IL‐2R, leading to its clustering at the base of protrusions to allow for receptor endocytosis.

    • Time lapse analysis reveals two stages for Arp2/3 activation during IL‐2R endocytosis: an early WAVE‐ and a late N‐WASP‐dependent one.

    • actin
    • cytokine receptor
    • dynamin
    • protrusion
    • wave regulatory complex
    • Received December 12, 2014.
    • Revision received May 27, 2015.
    • Accepted May 27, 2015.
    Cyril Basquin, Michaël Trichet, Helena Vihinen, Valérie Malardé, Thibault Lagache, Léa Ripoll, Eija Jokitalo, Jean‐Christophe Olivo‐Marin, Alexis Gautreau, Nathalie Sauvonnet