Mea6 Controls VLDL Transport Through the Coordinated Regulation of COPII Assembly
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Analysis of Trans Esnps Infers Regulatory Network Architecture
Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation. -
RNF11 at the Crossroads of Protein Ubiquitination
biomolecules Review RNF11 at the Crossroads of Protein Ubiquitination Anna Mattioni, Luisa Castagnoli and Elena Santonico * Department of Biology, University of Rome Tor Vergata, Via della ricerca scientifica, 00133 Rome, Italy; [email protected] (A.M.); [email protected] (L.C.) * Correspondence: [email protected] Received: 29 September 2020; Accepted: 8 November 2020; Published: 11 November 2020 Abstract: RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate evolution. RNF11 has drawn attention as a modulator of protein degradation by HECT E3 ligases. Indeed, the large number of substrates that are regulated by HECT ligases, such as ITCH, SMURF1/2, WWP1/2, and NEDD4, and their role in turning off the signaling by ubiquitin-mediated degradation, candidates RNF11 as the master regulator of a plethora of signaling pathways. Starting from the analysis of the primary sequence motifs and from the list of RNF11 protein partners, we summarize the evidence implicating RNF11 as an important player in modulating ubiquitin-regulated processes that are involved in transforming growth factor beta (TGF-β), nuclear factor-κB (NF-κB), and Epidermal Growth Factor (EGF) signaling pathways. This connection appears to be particularly significant, since RNF11 is overexpressed in several tumors, even though its role as tumor growth inhibitor or promoter is still controversial. The review highlights the different facets and peculiarities of this unconventional small RING-E3 ligase and its implication in tumorigenesis, invasion, neuroinflammation, and cancer metastasis. Keywords: Ring Finger Protein 11; HECT ligases; ubiquitination 1. -
Essential Genes and Their Role in Autism Spectrum Disorder
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. -
Murine SEC24D Can Substitute Functionally for SEC24C in Vivo
bioRxiv preprint doi: https://doi.org/10.1101/284398; this version posted March 22, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Functional Overlap Between Mouse SEC24C and SEC24D Murine SEC24D Can Substitute Functionally for SEC24C in vivo Elizabeth J. Adams1,2, Rami Khoriaty2,3, Anna Kiseleva1, Audrey C. A. Cleuren1,7, Kärt Tomberg1,4, Martijn A. van der Ent3, Peter Gergics4, K. Sue O’Shea5, Thomas L. Saunders3, David Ginsburg1-4,6,7 1From the Life Sciences Institute, 2Program in Cellular and Molecular Biology, 3Department of Internal Medicine, 4Departement of Human Genetics, 5Department of Cell and Developmental Biology, 6Department of Pediatrics and the 7Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109 ABSTRACT The COPII component SEC24 mediates the recruitment of transmembrane cargoes or cargo adaptors into newly forming COPII vesicles on the ER membrane. Mammalian genomes encode four Sec24 paralogs (Sec24a-d), with two subfamilies based on sequence homology (SEC24A/B and C/D), though little is known about their comparative functions and cargo-specificities. Complete deficiency for Sec24d results in very early embryonic lethality in mice (before the 8 cell stage), with later embryonic lethality (E 7.5) observed in Sec24c null mice. To test the potential overlap in function between SEC24C/D, we employed dual recombinase mediated cassette exchange to generate a Sec24cc-d allele, in which the C-terminal 90% of SEC24C has been replaced by SEC24D coding sequence. In contrast to the embryonic lethality at E7.5 of SEC24C-deficiency, Sec24cc-d/c-d pups survive to term, though dying shortly after birth. -
Mechanisms of Synaptic Plasticity Mediated by Clathrin Adaptor-Protein Complexes 1 and 2 in Mice
Mechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in mice Dissertation for the award of the degree “Doctor rerum naturalium” at the Georg-August-University Göttingen within the doctoral program “Molecular Biology of Cells” of the Georg-August University School of Science (GAUSS) Submitted by Ratnakar Mishra Born in Birpur, Bihar, India Göttingen, Germany 2019 1 Members of the Thesis Committee Prof. Dr. Peter Schu Institute for Cellular Biochemistry, (Supervisor and first referee) University Medical Center Göttingen, Germany Dr. Hans Dieter Schmitt Neurobiology, Max Planck Institute (Second referee) for Biophysical Chemistry, Göttingen, Germany Prof. Dr. med. Thomas A. Bayer Division of Molecular Psychiatry, University Medical Center, Göttingen, Germany Additional Members of the Examination Board Prof. Dr. Silvio O. Rizzoli Department of Neuro-and Sensory Physiology, University Medical Center Göttingen, Germany Dr. Roland Dosch Institute of Developmental Biochemistry, University Medical Center Göttingen, Germany Prof. Dr. med. Martin Oppermann Institute of Cellular and Molecular Immunology, University Medical Center, Göttingen, Germany Date of oral examination: 14th may 2019 2 Table of Contents List of abbreviations ................................................................................. 5 Abstract ................................................................................................... 7 Chapter 1: Introduction ............................................................................ -
S100A8 Transported by SEC23A Inhibits Metastatic Colonization Via
Sun et al. Cell Death and Disease (2020) 11:650 https://doi.org/10.1038/s41419-020-02835-w Cell Death & Disease ARTICLE Open Access S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy Zhiwei Sun1,2, Bin Zeng1,2,DoudouLiu1,2, Qiting Zhao1,2,JianyuWang1,2 and H. Rosie Xing2,3 Abstract Metastasis is the main cause of failure of cancer treatment. Metastatic colonization is regarded the most rate- limiting step of metastasis and is subjected to regulation by a plethora of biological factors and processes. On one hand, regulation of metastatic colonization by autophagy appears to be stage- and context-dependent, whereas mechanistic characterization remains elusive. On the other hand, interactions between the tumor cells and their microenvironment in metastasis have long been appreciated, whether the secretome of tumor cells can effectively reshape the tumor microenvironment has not been elucidated mechanistically. In the present study, we have identified “SEC23A-S1008-BECLIN1-autophagy axis” in the autophagic regulation of metastatic colonization step, a mechanism that tumor cells can exploit autophagy to exert self-restrain for clonogenic proliferation before the favorable tumor microenvironment is established. Specifically, we employed a paired lung-derived oligometastatic cell line (OL) and the homologous polymetastatic cell line (POL) from human melanoma cell line M14 that differ in colonization efficiency. We show that S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy. Furthermore, we verified the clinical relevance of our experimental findings by bioinformatics analysis of the expression of Sec23a and S100A8 and the clinical- pathological associations. We demonstrate that higher Sec23a and Atg5 expression levels appear to be protective factors and favorable diagnostic (TNM staging) and prognostic (overall survival) markers for skin cutaneous 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; melanoma (SKCM) and colon adenocarcinoma (COAD) patients. -
Consequences of Mutations in the Genes of the ER Export Machinery COPII in Vertebrates
Biomedical Sciences Publications Biomedical Sciences 1-22-2020 Consequences of mutations in the genes of the ER export machinery COPII in vertebrates Chung-Ling Lu Iowa State University, [email protected] Jinoh Kim Iowa State University, [email protected] Follow this and additional works at: https://lib.dr.iastate.edu/bms_pubs Part of the Cellular and Molecular Physiology Commons, Molecular Biology Commons, and the Molecular Genetics Commons The complete bibliographic information for this item can be found at https://lib.dr.iastate.edu/ bms_pubs/81. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Biomedical Sciences at Iowa State University Digital Repository. It has been accepted for inclusion in Biomedical Sciences Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Consequences of mutations in the genes of the ER export machinery COPII in vertebrates Abstract Coat protein complex II (COPII) plays an essential role in the export of cargo molecules such as secretory proteins, membrane proteins, and lipids from the endoplasmic reticulum (ER). In yeast, the COPII machinery is critical for cell viability as most COPII knockout mutants fail to survive. In mice and fish, homozygous knockout mutants of most COPII genes are embryonic lethal, reflecting the essentiality of the COPII machinery in the early stages of vertebrate development. In humans, COPII mutations, which are often hypomorphic, cause diseases having distinct clinical features. This is interesting as the fundamental cellular defect of these diseases, that is, failure of ER export, is similar. -
Site-1 Protease Deficiency Causes Human Skeletal Dysplasia Due to Defective Inter-Organelle Protein Trafficking
Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking Yuji Kondo, … , Patrick M. Gaffney, Lijun Xia JCI Insight. 2018;3(14):e121596. https://doi.org/10.1172/jci.insight.121596. Research Article Cell biology Genetics Graphical abstract Find the latest version: https://jci.me/121596/pdf RESEARCH ARTICLE Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking Yuji Kondo,1 Jianxin Fu,1,2 Hua Wang,3 Christopher Hoover,1,4 J. Michael McDaniel,1 Richard Steet,5 Debabrata Patra,6 Jianhua Song,1 Laura Pollard,7 Sara Cathey,7 Tadayuki Yago,1 Graham Wiley,8 Susan Macwana,8 Joel Guthridge,8 Samuel McGee,1 Shibo Li,3 Courtney Griffin,1 Koichi Furukawa,9 Judith A. James,8 Changgeng Ruan,2 Rodger P. McEver,1,4 Klaas J. Wierenga,3 Patrick M. Gaffney,8 and Lijun Xia1,2,4 1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. 2Jiangsu Institute of Hematology, MOH Key Laboratory of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China. 3Department of Pediatrics and 4Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. 5Complex Carbohydrate Research Center, University of Georgia, Georgia, Athens, USA. 6Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. 7Greenwood Genetic Center, Greenwood, South Carolina, USA. 8Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. 9Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya, Japan. -
ER-To-Golgi Trafficking and Its Implication in Neurological Diseases
cells Review ER-to-Golgi Trafficking and Its Implication in Neurological Diseases 1,2, 1,2 1,2, Bo Wang y, Katherine R. Stanford and Mondira Kundu * 1 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; [email protected] (B.W.); [email protected] (K.R.S.) 2 Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA * Correspondence: [email protected]; Tel.: +1-901-595-6048 Present address: School of Life Sciences, Xiamen University, Xiamen 361102, China. y Received: 21 November 2019; Accepted: 7 February 2020; Published: 11 February 2020 Abstract: Membrane and secretory proteins are essential for almost every aspect of cellular function. These proteins are incorporated into ER-derived carriers and transported to the Golgi before being sorted for delivery to their final destination. Although ER-to-Golgi trafficking is highly conserved among eukaryotes, several layers of complexity have been added to meet the increased demands of complex cell types in metazoans. The specialized morphology of neurons and the necessity for precise spatiotemporal control over membrane and secretory protein localization and function make them particularly vulnerable to defects in trafficking. This review summarizes the general mechanisms involved in ER-to-Golgi trafficking and highlights mutations in genes affecting this process, which are associated with neurological diseases in humans. Keywords: COPII trafficking; endoplasmic reticulum; Golgi apparatus; neurological disease 1. Overview Approximately one-third of all proteins encoded by the mammalian genome are exported from the endoplasmic reticulum (ER) and transported to the Golgi apparatus, where they are sorted for delivery to their final destination in membrane compartments or secretory vesicles [1]. -
Cryo-Tomography of Coat Complexes ISSN 2059-7983
research papers Visualizing membrane trafficking through the electron microscope: cryo-tomography of coat complexes ISSN 2059-7983 Evgenia A. Markova and Giulia Zanetti* Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX, England. Received 8 March 2019 *Correspondence e-mail: [email protected] Accepted 12 April 2019 Coat proteins mediate vesicular transport between intracellular compartments, Keywords: cryo-electron tomography; which is essential for the distribution of molecules within the eukaryotic cell. three-dimensional reconstruction; coat proteins; The global arrangement of coat proteins on the membrane is key to their vesicular transport; COPII; subtomogram function, and cryo-electron tomography and subtomogram averaging have been averaging. used to study membrane-bound coat proteins, providing crucial structural insight. This review outlines a workflow for the structural elucidation of coat proteins, incorporating recent developments in the collection and processing of cryo-electron tomography data. Recent work on coat protein I, coat protein II and retromer performed on in vitro reconstitutions or in situ is summarized. These studies have answered long-standing questions regarding the mechanisms of membrane binding, polymerization and assembly regulation of coat proteins. 1. Introduction Recent advances in cryo-electron microscopy (cryo-EM) have enabled numerous high-resolution studies which have addressed long-standing structural biology questions. The large body of cryo-EM work carried out for protein structure characterization has utilized single-particle electron micro- scopy (Cheng, 2018). Recently, developments in hardware, data collection and data processing have placed cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) at the forefront of structural studies of repetitive assemblies, reaching resolutions comparable to those of single-particle EM (Schur et al., 2016; Wan et al., 2017; Hutchings et al., 2018; Dodonova et al., 2017; Himes & Zhang, 2018). -
Vesicular and Uncoated Rab1-Dependent Cargo Carriers Facilitate ER to Golgi Transport Laura M
© 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs239814. doi:10.1242/jcs.239814 RESEARCH ARTICLE Vesicular and uncoated Rab1-dependent cargo carriers facilitate ER to Golgi transport Laura M. Westrate1,*, Melissa J. Hoyer2,3,*, Michael J. Nash2 and Gia K. Voeltz2,3,‡ ABSTRACT next recruits the heterodimer ‘inner coat’ complex Sec23/Sec24, Secretory cargo is recognized, concentrated and trafficked from which stabilizes membrane curvature and recruits cargo through the endoplasmic reticulum (ER) exit sites (ERES) to the Golgi. Cargo cargo binding sites on Sec24 (Bi et al., 2002; Kuehn et al., 1998; export from the ER begins when a series of highly conserved COPII Miller et al., 2002, 2003). The inner coat recruits the heterotetramer ‘ ’ coat proteins accumulate at the ER and regulate the formation of outer coat complex composed of Sec13/Sec31, resulting in the cargo-loaded COPII vesicles. In animal cells, capturing live de novo formation of a fully formed COPII-coated transport vesicle that cargo trafficking past this point is challenging; it has been difficult to delivers incorporated cargo to the Golgi complex via anterograde discriminate whether cargo is trafficked to the Golgi in a COPII-coated trafficking from the ER (Kirk and Ward, 2007; Lederkremer et al., vesicle. Here, we describe a recently developed live-cell cargo export 2001; Lee et al., 2004; Rossanese et al., 1999; Stagg et al., 2006). system that can be synchronously released from ERES to illustrate de Many of these studies have been performed in yeast cells because of novo trafficking in animal cells. -
Single Cell Derived Clonal Analysis of Human Glioblastoma Links
SUPPLEMENTARY INFORMATION: Single cell derived clonal analysis of human glioblastoma links functional and genomic heterogeneity ! Mona Meyer*, Jüri Reimand*, Xiaoyang Lan, Renee Head, Xueming Zhu, Michelle Kushida, Jane Bayani, Jessica C. Pressey, Anath Lionel, Ian D. Clarke, Michael Cusimano, Jeremy Squire, Stephen Scherer, Mark Bernstein, Melanie A. Woodin, Gary D. Bader**, and Peter B. Dirks**! ! * These authors contributed equally to this work.! ** Correspondence: [email protected] or [email protected]! ! Supplementary information - Meyer, Reimand et al. Supplementary methods" 4" Patient samples and fluorescence activated cell sorting (FACS)! 4! Differentiation! 4! Immunocytochemistry and EdU Imaging! 4! Proliferation! 5! Western blotting ! 5! Temozolomide treatment! 5! NCI drug library screen! 6! Orthotopic injections! 6! Immunohistochemistry on tumor sections! 6! Promoter methylation of MGMT! 6! Fluorescence in situ Hybridization (FISH)! 7! SNP6 microarray analysis and genome segmentation! 7! Calling copy number alterations! 8! Mapping altered genome segments to genes! 8! Recurrently altered genes with clonal variability! 9! Global analyses of copy number alterations! 9! Phylogenetic analysis of copy number alterations! 10! Microarray analysis! 10! Gene expression differences of TMZ resistant and sensitive clones of GBM-482! 10! Reverse transcription-PCR analyses! 11! Tumor subtype analysis of TMZ-sensitive and resistant clones! 11! Pathway analysis of gene expression in the TMZ-sensitive clone of GBM-482! 11! Supplementary figures and tables" 13" "2 Supplementary information - Meyer, Reimand et al. Table S1: Individual clones from all patient tumors are tumorigenic. ! 14! Fig. S1: clonal tumorigenicity.! 15! Fig. S2: clonal heterogeneity of EGFR and PTEN expression.! 20! Fig. S3: clonal heterogeneity of proliferation.! 21! Fig.