DOCSLIB.ORG

The Type 2 Diabetes Gene Product STARD10 Is a Phosphoinositide Binding Protein That Controls Insulin Secretory Granule Biogenesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Type 2 Diabetes Gene Product STARD10 Is a Phosphoinositide Binding Protein That Controls Insulin Secretory Granule Biogenesis Carrat, G., Haythorne, E., Tomas, A., Haataja, L., Muller, A., Arvan, P., Piunti, A., Cheng, K., Huang, M., Pullen, T. J., Georgiadou, E., Stylianides, T., Amirruddin, N. S., Salem, V., Distaso, W., Cakebread, A., Heesom, K. J., Lewis, P. A., Hodson, D. J., ... Rutter, G. A. (2020). The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis. Molecular metabolism, 40, [101015]. https://doi.org/10.1016/j.molmet.2020.101015 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1016/j.molmet.2020.101015 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Elsevier at https://www.sciencedirect.com/science/article/pii/S2212877820300892?via%3Dihub. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Original Article The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis Gaelle R. Carrat 1, Elizabeth Haythorne 1, Alejandra Tomas 1, Leena Haataja 2, Andreas Müller 3,4,5,6, Peter Arvan 2, Alexandra Piunti 1,7, Kaiying Cheng 8, Mutian Huang 1, Timothy J. Pullen 1,9, Eleni Georgiadou 1, Theodoros Stylianides 10, Nur Shabrina Amirruddin 11,12, Victoria Salem 1,13, Walter Distaso 14, Andrew Cakebread 15, Kate J. Heesom 16, Philip A. Lewis 16, David J. Hodson 17,18,19, Linford J. Briant 20, Annie C.H. Fung 21, Richard B. Sessions 22, Fabien Alpy 23, Alice P.S. Kong 21, Peter I. Benke 24, Federico Torta 24, Adrian Kee Keong Teo 11,12,25, Isabelle Leclerc 1, Michele Solimena 3,4,5,6, Dale B. Wigley 8, Guy A. Rutter 1,* ABSTRACT Objective: Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the b-cell, impaired glucose-induced insulin secretion, and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids and thus the pathways through which STARD10 regulates b-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the b-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. Methods: We used isolated islets from mice deleted selectively in the b-cell for Stard10 (bStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. Results: bStard10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3’ position. Lipidomic analysis of bStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in bStard10KO islets. Conclusion: Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing. Ó 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Keywords Type 2 diabetes; Pancreatic b-cell; Lipid transporter; Insulin granule biogenesis; Phosphoinositides 1Section of Cell Biology and Functional Genomics, Imperial College London, du Cane Road, London, W12 0NN, UK 2Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA 3Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany 4Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, University Hospital Carl Gustav Carus and Faculty of Medicine of the TU Dresden, Dresden, Germany 5German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany 6Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany 7Lille 1 University-Science and Technology, Cité Scientifique, 59655, Villeneuve d’Ascq Cedex, France 8Section of Structural Biology, Department of Medicine, Imperial College London, London, UK 9Department of Diabetes, Faculty of Life Science and Medicine, King’s College London, London, UK 10Loughborough University, Centre of Innovative and Collaborative Construction Engineering, Leicestershire, LE11 3TU, UK 11Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, 138673, Singapore 12Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore 13Section of Investigative Medicine, Department of Medicine, Imperial College London, du Cane Road, London, W12 0NN, UK 14Imperial College Business School, Imperial College London, Exhibition Road, London, SW7 2AZ, UK 15London Metallomics Facility, King’s College London, Strand, London, WC2R 2LS, UK 16Proteomics Facility, University of Bristol, Bristol, UK 17Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Bir- mingham, UK 18Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, UK 19Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, Midlands, UK 20Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK 21Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong 22School of Biochemistry, Faculty of Life Sciences, University of Bristol, Bristol, BS8 1TD, UK 23Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U1258, Centre National de la Recherche Scientifique (CNRS), UMR 7104, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France 24Singapore Lipidomics Incubator, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Mdical Drive, Singapore, 117596, Singapore 25Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore *Corresponding author. þ44 (0)20 7594 3340. E-mail: [email protected] (G.A. Rutter). Received February 28, 2020 Revision received April 24, 2020 Accepted May 5, 2020 Available online 13 May 2020 https://doi.org/10.1016/j.molmet.2020.101015 MOLECULAR METABOLISM 40 (2020) 101015 Ó 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1 www.molecularmetabolism.com Original Article Abbreviations PI(3)P phosphatidylinositol 3-phosphate PI(4,5)P2 PIP2, phosphatidylinositol 4,5-bisphosphate BUDE Bristol University Docking Engine PI(5)P phosphatidylinositol 5-phosphate GFP Green Fluorescent Protein PIP phosphatidylinositol phosphate, phosphatidylinositide GWAS Genome-Wide Association Study Pip4k2c phosphatidylinositol 5-phosphate 4-kinase type-2 gamma þ KATP ATP-sensitive K channels Pirt phosphoinositide-interacting regulator of transient receptor HRP Horseradish Peroxidase potential channels Kir6.2, Kcnj11 Potassium Inwardly Rectifying Channel Subfamily J RNAseq RNA sequencing Member 11 Ptbp1 polypyrimidine tract-binding protein 1 KOMP NIH Knockout Mouse Project Slc30a8 ZnT8, Solute Carrier Family 30 Member 8 ICP/MS inductively coupled plasma mass spectrometry SNARE Soluble N-ethylmaleimide sensitive factor Attachment protein IMPC International Mouse Phenotyping Consortium Receptor LPC lysophosphatidylcholine STARD10 StAR Related Lipid Transfer Domain Containing 10 MBP Maltose Binding Protein Syt1 synaptotagmin 1 PC phosphatidylcholine Sytl4 synaptotagmin-like 4, granuphilin PE phosphatidylethanolamine TMT Tandem Mass Tag PI phosphatidylinositol TRP transient receptor potential 1. INTRODUCTION membranes, remain unknown. We, therefore, examined in detail here the role of STARD10 in controlling the lipid composition, granule Diabetes mellitus is characterised by high blood glucose and currently maturation, proinsulin processing, and metal ion homeostasis in the affects around 8.5% of the population worldwide. Normal glucose mouse b-cell. We reveal an unexpected role for STARD10 in binding homeostasis requires the processing of proinsulin and the storage of inositol phospholipids which may contribute to both secretory
Load more

Recommended publications
  • Regulation and Essentiality of the Star-Related Lipid Transfer (START
    crossmark THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 291, NO. 46, pp. 24280–24292, November 11, 2016 Author’s Choice © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Regulation and Essentiality of the StAR-related Lipid Transfer (START) Domain-containing Phospholipid Transfer Protein PFA0210c in Malaria Parasites* Received for publication, May 26, 2016, and in revised form, September 23, 2016 Published, JBC Papers in Press, October 2, 2016, DOI 10.1074/jbc.M116.740506 Ross J. Hill‡1, Alessa Ringel‡2, Ellen Knuepfer‡, Robert W. Moon§, Michael J. Blackman‡¶, and Christiaan van Ooij‡3 From the ‡The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA and the Departments of §Infection and Immunity and ¶Pathogen Molecular Biology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom Downloaded from Edited by George Carman StAR-related lipid transfer (START) domains are phospho- Phospholipid transfer proteins play important roles in the lipid- or sterol-binding modules that are present in many pro- trafficking of phospholipids within eukaryotic cells (1). One teins. START domain-containing proteins (START proteins) subset of phospholipid transfer proteins is represented by a http://www.jbc.org/ play important functions in eukaryotic cells, including the redis- group of proteins containing a StAR-related (START)4 lipid- tribution of phospholipids to subcellular compartments and transfer domain, which mediates the binding to lipids or sterols delivering sterols to the mitochondrion for steroid synthesis. and can promote their transfer between membranes. Although How the activity of the START domain is regulated remains sequence similarity between different START domains can be unknown for most of these proteins.
    [Show full text]
  • Differential Expression and Co-Expression Gene Networks Reveal Candidate Biomarkers of Boar Taint in Non-Castrated Pigs
    Downloaded from orbit.dtu.dk on: Oct 06, 2021 Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs Drag, Markus; Skinkyté-Juskiené, Ruta; Do, Duy N.; Kogelman, Lisette J. A.; Kadarmideen, Haja N. Published in: Scientific Reports Link to article, DOI: 10.1038/s41598-017-11928-0 Publication date: 2017 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Drag, M., Skinkyté-Juskiené, R., Do, D. N., Kogelman, L. J. A., & Kadarmideen, H. N. (2017). Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs. Scientific Reports, 7(1), [12205]. https://doi.org/10.1038/s41598-017-11928-0 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. www.nature.com/scientificreports OPEN Differential expression and co- expression gene networks reveal candidate biomarkers of boar taint Received: 8 November 2016 Accepted: 1 September 2017 in non-castrated pigs Published: xx xx xxxx Markus Drag 1,4, Ruta Skinkyté-Juskiené 1, Duy N.
    [Show full text]
  • Refined Genetic Mapping of Autosomal Recessive Chronic Distal Spinal Muscular Atrophy to Chromosome 11Q13.3 and Evidence of Link
    European Journal of Human Genetics (2004) 12, 483–488 & 2004 Nature Publishing Group All rights reserved 1018-4813/04 $30.00 www.nature.com/ejhg ARTICLE Refined genetic mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13.3 and evidence of linkage disequilibrium in European families Louis Viollet*,1, Mohammed Zarhrate1, Isabelle Maystadt1, Brigitte Estournet-Mathiaut2, Annie Barois2, Isabelle Desguerre3, Miche`le Mayer4, Brigitte Chabrol5, Bruno LeHeup6, Veronica Cusin7, Thierry Billette de Villemeur8, Dominique Bonneau9, Pascale Saugier-Veber10, Anne Touzery-de Villepin11, Anne Delaubier12, Jocelyne Kaplan1, Marc Jeanpierre13, Joshue´ Feingold1 and Arnold Munnich1 1Unite´ de Recherches sur les Handicaps Ge´ne´tiques de l’Enfant, INSERM U393. Hoˆpital Necker Enfants Malades, 149 rue de Se`vres, 75743 Paris Cedex 15, France; 2Service de Neurope´diatrie, Re´animation et Re´e´ducation Neuro-respiratoire, Hoˆpital Raymond Poincare´, 92380 Garches, France; 3Service de Neurope´diatrie, Hoˆpital Necker Enfants Malades, 149 rue de Se`vres, 75743 Paris Cedex 15, France; 4Service de Neurope´diatrie, Hoˆpital Saint Vincent de Paul, 82 boulevard Denfert Rochereau, 75674 Paris Cedex 14, France; 5Service de Neurope´diatrie, Hoˆpital Timone Enfants, 264 rue Saint Pierre 13385 Marseille Cedex, France; 6Secteur de De´veloppement et Ge´ne´tique, CHR de Nancy, Hoˆpitaux de Brabois, Rue du Morvan, 54511 Vandoeuvre Cedex, France; 7Service de Ge´ne´tique de Dijon, Hoˆpital d’Enfants, 2 blvd du Mare´chal de Lattre de Tassigny,
    [Show full text]
  • The Type 2 Diabetes Gene Product STARD10 Is a Phosphoinositide Binding Protein That Controls Insulin Secretory Granule Biogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.25.007286; this version posted March 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis Gaelle R. Carrat1, Elizabeth Haythorne1, Alejandra Tomas1, Leena Haataja2, Andreas Müller3,4,5,6, Peter Arvan2, Alexandra Piunti1,7, Kaiying Cheng8, Mutian Huang1, Timothy J. Pullen1,9, Eleni Georgiadou1, Theodoros Stylianides10, Nur Shabrina Amirruddin11,12, Victoria Salem 1,13, Walter Distaso14, Andrew Cakebread 15, Kate J.Heesom16, Philip A. Lewis16, David J. Hodson17, Linford J. Briant18, Annie C.H. Fung19, Richard B. Sessions20, Fabien Alpy21, Alice P.S. Kong19, Peter I. Benke22, Federico Torta22, Adrian Kee Keong Teo11,12, 23, Isabelle Leclerc1, Michele Solimena 3,4,5,6 , Dale B. Wigley8 and Guy A. Rutter1* 1 - Section of Cell Biology and Functional Genomics, Imperial College London, du Cane Road, London W12 0NN, UK. 2 - Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. 3 - Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany. 4 - Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich, University Hospital Carl Gustav Carus and Faculty of Medicine of the TU Dresden, Dresden, Germany. 5 - German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
    [Show full text]
  • Altered Gene Expression in Circulating Immune Cells Following a 24-Hour Passive Dehydration
    University of Connecticut OpenCommons@UConn Master's Theses University of Connecticut Graduate School 5-10-2020 Altered Gene Expression in Circulating Immune Cells Following a 24-Hour Passive Dehydration Aidan Fiol [email protected] Follow this and additional works at: https://opencommons.uconn.edu/gs_theses Recommended Citation Fiol, Aidan, "Altered Gene Expression in Circulating Immune Cells Following a 24-Hour Passive Dehydration" (2020). Master's Theses. 1480. https://opencommons.uconn.edu/gs_theses/1480 This work is brought to you for free and open access by the University of Connecticut Graduate School at OpenCommons@UConn. It has been accepted for inclusion in Master's Theses by an authorized administrator of OpenCommons@UConn. For more information, please contact [email protected]. Altered Gene Expression in Circulating Immune Cells Following a 24- Hour Passive Dehydration Aidan Fiol B.S., University of Connecticut, 2018 A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science At the University of Connecticut 2020 i copyright by Aidan Fiol 2020 ii APPROVAL PAGE Master of Science Thesis Altered Gene Expression in Circulating Immune Cells Following a 24- Hour Passive Dehydration Presented by Aidan Fiol, B.S. Major Advisor__________________________________________________________________ Elaine Choung-Hee Lee, Ph.D. Associate Advisor_______________________________________________________________ Douglas J. Casa, Ph.D. Associate Advisor_______________________________________________________________ Robert A. Huggins, Ph.D. University of Connecticut 2020 iii ACKNOWLEDGEMENTS I’d like to thank my committee members. Dr. Lee, you have been an amazing advisor, mentor and friend to me these past few years. Your advice, whether it was how to be a better writer or scientist, or just general life advice given on our way to get coffee, has helped me grow as a researcher and as a person.
    [Show full text]
  • The Phosphoprotein Stard10 Is Overexpressed in Breast Cancer and Cooperates with Erbb Receptors in Cellular Transformation
    [CANCER RESEARCH 64, 3538–3544, May 15, 2004] The Phosphoprotein StarD10 Is Overexpressed in Breast Cancer and Cooperates with ErbB Receptors in Cellular Transformation Monilola A. Olayioye,1 Peter Hoffmann,2 Thomas Pomorski,3 Jane Armes,4 Richard J. Simpson,5 Bruce E. Kemp,2 Geoffrey J. Lindeman,1 and Jane E. Visvader1 1The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Royal Melbourne Hospital, Parkville, Victoria, Australia; 2St. Vincent’s Institute of Medical Research, St. Vincent’s Hospital, Victoria, Australia; 3Humboldt-University Berlin, Institute of Biology and Biophysics, Berlin, Germany; 4Molecular Pathology Laboratory, Victorian Breast Cancer Research Consortium, Department of Pathology, University of Melbourne, Victoria, Australia; and 5Joint Proteomics Laboratory, Ludwig Institute for Cancer Research and The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia ABSTRACT tion of the phosphatidylinositol 3-kinase (PI3K) pathway (15, 16). Signaling through PI3K plays an important role in cellular survival by We have identified that StarD10, a member of the START protein phosphorylating and inactivating growth-inhibitory and proapoptotic family, is overexpressed in both mouse and human breast tumors. proteins, including the FOXO transcription factors (17). In addition, StarD10 was initially discovered on the basis of its cross-reactivity with a phosphoserine-specific antibody in mammary tumors from Neu/ErbB2 the ErbB2 and ErbB3 receptors recruit the adaptor proteins Shc and transgenic mice and subsequently isolated from SKBR3 human breast Grb2 (16, 18, 19), resulting in stimulation of the Ras-Raf-mitogen- carcinoma cells using a multistep biochemical purification strategy. We activated protein kinase pathway (20, 21), which has been implicated have shown that StarD10 is capable of binding lipids.
    [Show full text]
  • A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion
    BASIC RESEARCH www.jasn.org A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion † ‡ | Annekatrin Aue,* Christian Hinze,* Katharina Walentin,* Janett Ruffert,* Yesim Yurtdas,*§ | Max Werth,* Wei Chen,* Anja Rabien,§ Ergin Kilic,¶ Jörg-Dieter Schulzke,** †‡ Michael Schumann,** and Kai M. Schmidt-Ott* *Max Delbrueck Center for Molecular Medicine, Berlin, Germany; †Experimental and Clinical Research Center, and Departments of ‡Nephrology, §Urology, ¶Pathology, and **Gastroenterology, Charité Medical University, Berlin, Germany; and |Berlin Institute of Urologic Research, Berlin, Germany ABSTRACT Grainyhead transcription factors control epithelial barriers, tissue morphogenesis, and differentiation, but their role in the kidney is poorly understood. Here, we report that nephric duct, ureteric bud, and collecting duct epithelia express high levels of grainyhead-like homolog 2 (Grhl2) and that nephric duct lumen expansion is defective in Grhl2-deficient mice. In collecting duct epithelial cells, Grhl2 inactivation impaired epithelial barrier formation and inhibited lumen expansion. Molecular analyses showed that GRHL2 acts as a transcrip- tional activator and strongly associates with histone H3 lysine 4 trimethylation. Integrating genome-wide GRHL2 binding as well as H3 lysine 4 trimethylation chromatin immunoprecipitation sequencing and gene expression data allowed us to derive a high-confidence GRHL2 target set. GRHL2 transactivated a group of genes including Ovol2, encoding the ovo-like 2 zinc finger transcription factor, as well as E-cadherin, claudin 4 (Cldn4), and the small GTPase Rab25. Ovol2 induction alone was sufficient to bypass the requirement of Grhl2 for E-cadherin, Cldn4,andRab25 expression. Re-expression of either Ovol2 or a combination of Cldn4 and Rab25 was sufficient to rescue lumen expansion and barrier formation in Grhl2-deficient collecting duct cells.
    [Show full text]
  • Intracellular Cholesterol Transport Proteins: Roles in Health and Disease Soffientini, Ugo; Graham, Annette
    Intracellular cholesterol transport proteins: roles in health and disease Soffientini, Ugo; Graham, Annette Published in: Clinical Science DOI: 10.1042/CS20160339 Publication date: 2016 Document Version Author accepted manuscript Link to publication in ResearchOnline Citation for published version (Harvard): Soffientini, U & Graham, A 2016, 'Intracellular cholesterol transport proteins: roles in health and disease', Clinical Science, vol. 130, no. 21, pp. 1843-1859. https://doi.org/10.1042/CS20160339 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Take down policy If you believe that this document breaches copyright please view our takedown policy at https://edshare.gcu.ac.uk/id/eprint/5179 for details of how to contact us. Download date: 26. Sep. 2021 Intracellular Cholesterol Transport Proteins: Roles in Health and Disease Ugo Soffientini§ and Annette Graham* Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, United Kingdom *Corresponding Author: Professor Annette Graham, Dept of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, 70 Cowcaddens Road, Glasgow G4 0BA, UK T: +44(0) 141 331 3722 F: +44(0) 141 331 3208 E: [email protected] §Present Address: Dr Ugo Soffientini, Jarrett Building, Veterinary Research Facility, University of Glasgow, Garscube, GlasgowG61 1QH, UK. Abstract Effective cholesterol homeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, while loss of these elegant, tightly regulated homeostatic responses is integral to disease pathologies.
    [Show full text]
  • Supplementary Table 1 Double Treatment Vs Single Treatment
    Supplementary table 1 Double treatment vs single treatment Probe ID Symbol Gene name P value Fold change TC0500007292.hg.1 NIM1K NIM1 serine/threonine protein kinase 1.05E-04 5.02 HTA2-neg-47424007_st NA NA 3.44E-03 4.11 HTA2-pos-3475282_st NA NA 3.30E-03 3.24 TC0X00007013.hg.1 MPC1L mitochondrial pyruvate carrier 1-like 5.22E-03 3.21 TC0200010447.hg.1 CASP8 caspase 8, apoptosis-related cysteine peptidase 3.54E-03 2.46 TC0400008390.hg.1 LRIT3 leucine-rich repeat, immunoglobulin-like and transmembrane domains 3 1.86E-03 2.41 TC1700011905.hg.1 DNAH17 dynein, axonemal, heavy chain 17 1.81E-04 2.40 TC0600012064.hg.1 GCM1 glial cells missing homolog 1 (Drosophila) 2.81E-03 2.39 TC0100015789.hg.1 POGZ Transcript Identified by AceView, Entrez Gene ID(s) 23126 3.64E-04 2.38 TC1300010039.hg.1 NEK5 NIMA-related kinase 5 3.39E-03 2.36 TC0900008222.hg.1 STX17 syntaxin 17 1.08E-03 2.29 TC1700012355.hg.1 KRBA2 KRAB-A domain containing 2 5.98E-03 2.28 HTA2-neg-47424044_st NA NA 5.94E-03 2.24 HTA2-neg-47424360_st NA NA 2.12E-03 2.22 TC0800010802.hg.1 C8orf89 chromosome 8 open reading frame 89 6.51E-04 2.20 TC1500010745.hg.1 POLR2M polymerase (RNA) II (DNA directed) polypeptide M 5.19E-03 2.20 TC1500007409.hg.1 GCNT3 glucosaminyl (N-acetyl) transferase 3, mucin type 6.48E-03 2.17 TC2200007132.hg.1 RFPL3 ret finger protein-like 3 5.91E-05 2.17 HTA2-neg-47424024_st NA NA 2.45E-03 2.16 TC0200010474.hg.1 KIAA2012 KIAA2012 5.20E-03 2.16 TC1100007216.hg.1 PRRG4 proline rich Gla (G-carboxyglutamic acid) 4 (transmembrane) 7.43E-03 2.15 TC0400012977.hg.1 SH3D19
    [Show full text]
  • And Tetranucleotide Short Tandem Repeats N
    Nazaripanah et al. Human Genomics (2018) 12:17 https://doi.org/10.1186/s40246-018-0149-3 PRIMARYRESEARCH Open Access Genome-scale portrait and evolutionary significance of human-specific core promoter tri- and tetranucleotide short tandem repeats N. Nazaripanah1, F. Adelirad1, A. Delbari1, R. Sahaf1, T. Abbasi-Asl2 and M. Ohadi1* Abstract Background: While there is an ongoing trend to identify single nucleotide substitutions (SNSs) that are linked to inter/intra-species differences and disease phenotypes, short tandem repeats (STRs)/microsatellites may be of equal (if not more) importance in the above processes. Genes that contain STRs in their promoters have higher expression divergence compared to genes with fixed or no STRs in the gene promoters. In line with the above, recent reports indicate a role of repetitive sequences in the rise of young transcription start sites (TSSs) in human evolution. Results: Following a comparative genomics study of all human protein-coding genes annotated in the GeneCards database, here we provide a genome-scale portrait of human-specific short- and medium-size (≥ 3-repeats) tri- and tetranucleotide STRs and STR motifs in the critical core promoter region between − 120 and + 1 to the TSS and evidence of skewing of this compartment in reference to the STRs that are not human-specific (Levene’s test p <0. 001). Twenty-five percent and 26% enrichment of human-specific transcripts was detected in the tri and tetra human-specific compartments (mid-p < 0.00002 and mid-p < 0.002, respectively). Conclusion: Our findings provide the first evidence of genome-scale skewing of STRs at a specific region of the human genome and a link between a number of these STRs and TSS selection/transcript specificity.
    [Show full text]
  • Chromatin 3D Interaction Analysis of the STARD10 Locus Unveils FCHSD2 As a New Regulator of Insulin Secretion
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.31.017707; this version posted April 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion Ming Hu1, Inês Cebola2, Gaelle Carrat1, Shuying Jiang1, Sameena Nawaz3 Amna Khamis4, Mickael Canouil4, Philippe Froguel4, Anke Schulte5, Michele Solimena6, Mark Ibberson7, Piero Marchetti8, Fabian L. Cardenas-Diaz9, Paul J. Gadue9, Benoit Hastoy3, Leonardo Alemeida-Souza10, Harvey McMahon11 and Guy A. Rutter1,12* 1Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. 2Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. 3Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE Oxford, 4Univ. Lille, CNRS, CHU Lille, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France. 5Sanofi-Aventis Deutschland GmbH, 65926 Frankfurt am Main, Germany 6Paul Langerhans Institute of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany 7Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland 8Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy 9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; and Centre for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, PA.
    [Show full text]
  • REVIEW the Mammalian START Domain Protein Family in Lipid
    257 REVIEW The mammalian START domain protein family in lipid transport in health and disease Barbara J Clark Department of Biochemistry and Molecular Biology, and the Center for Genetics and Molecular Medicine, School of Medicine, University of Louisville, Louisville, Kentucky 40292, USA (Correspondence should be addressed to B J Clark; Email: [email protected]) Abstract Lipid transfer proteins of the steroidogenic acute regulatory START domain protein family are not well established. protein-related lipid transfer (START) domain family are Recent research has focused on characterizing the cell-type defined by the presence of a conserved w210 amino acid distribution and regulation of the START proteins, examin- sequence that folds into an a/b helix-grip structure forming a ing the specificity and directionality of lipid transport, and hydrophobic pocket for ligand binding. The mammalian identifying disease states associated with dysregulation of START proteins bind diverse ligands, such as cholesterol, START protein expression. This review summarizes the oxysterols, phospholipids, sphingolipids, and possibly fatty current concepts of the proposed physiological and patho- acids, and have putative roles in non-vesicular lipid transport, logical roles for the mammalian START domain proteins in thioesterase enzymatic activity, and tumor suppression. cholesterol and lipid trafficking. However, the biological functions of many members of the Journal of Endocrinology (2012) 212, 257–275 Introduction organized membrane region for signaling and other functions (Lingwood & Simons 2010). Changes in ER membrane Lipid transport proteins play an important role in non- cholesterol levels signal for changes in gene expression leading vesicular trafficking of cholesterol, phospholipids, and to altered cholesterol metabolism while transport of sphingolipids between biological membranes to help maintain cholesterol to mitochondria is required for production of the proper cholesterol:phospholipid:sphingolipid distribution steroid hormones and bile acids.
    [Show full text]