CORVET, CHEVI and HOPS – Multisubunit Tethers of the Endo
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Diagnosing Platelet Secretion Disorders: Examples Cases
Diagnosing platelet secretion disorders: examples cases Martina Daly Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Disclosures for Martina Daly In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board Platelet granule release Agonists (FIIa, Collagen, ADP) Signals Activation Shape change Membrane fusion Release of granule contents Platelet storage organelles lysosomes a granules Enzymes including cathepsins Adhesive proteins acid hydrolases Clotting factors and their inhibitors Fibrinolytic factors and their inhibitors Proteases and antiproteases Growth and mitogenic factors Chemokines, cytokines Anti-microbial proteins Membrane glycoproteins dense (d) granules ADP/ATP Serotonin histamine inorganic polyphosphate Platelet a-granule contents Type Prominent components Membrane glycoproteins GPIb, aIIbb3, GPVI Clotting factors VWF, FV, FXI, FII, Fibrinogen, HMWK, FXIII? Clotting inhibitors TFPI, protein S, protease nexin-2 Fibrinolysis components PAI-1, TAFI, a2-antiplasmin, plasminogen, uPA Other protease inhibitors a1-antitrypsin, a2-macroglobulin -
A Yeast Phenomic Model for the Gene Interaction Network Modulating
Louie et al. Genome Medicine 2012, 4:103 http://genomemedicine.com/content/4/12/103 RESEARCH Open Access A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis Raymond J Louie3†, Jingyu Guo1,2†, John W Rodgers1, Rick White4, Najaf A Shah1, Silvere Pagant3, Peter Kim3, Michael Livstone5, Kara Dolinski5, Brett A McKinney6, Jeong Hong2, Eric J Sorscher2, Jennifer Bryan4, Elizabeth A Miller3* and John L Hartman IV1,2* Abstract Background: The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) accounts for most of the disease. In cell models, CFTR-ΔF508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-ΔF508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-ΔF would manifest phenotypically. Methods: To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC transporter, we employed yeast genetics to develop a ‘phenomic’ model, in which the CFTR-ΔF508-equivalent residue of a yeast homolog is mutated (Yor1-ΔF670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-ΔF undergoes protein misfolding and has reduced half-life, analogous to CFTR-ΔF. Gene interaction was then assessed quantitatively by growth curves for approximately 5,000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1. -
Vps8 Overexpression Inhibits HOPS- Dependent Trafficking Routes By
RESEARCH ADVANCE Vps8 overexpression inhibits HOPS- dependent trafficking routes by outcompeting Vps41/Lt Pe´ ter Lo˝ rincz1,2*, Lili Anna Kene´ z1, Sarolta To´ th1, Vikto´ ria Kiss3,A´ gnes Varga1, Tama´ s Csizmadia1, Zso´ fia Simon-Vecsei1, Ga´ bor Juha´ sz1,3* 1Department of Anatomy, Cell and Developmental Biology, Eo¨ tvo¨ s Lora´nd University, Budapest, Hungary; 2Premium Postdoctoral Research Program, Hungarian Academy of Sciences, Budapest, Hungary; 3Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary Abstract Two related multisubunit tethering complexes promote endolysosomal trafficking in all eukaryotes: Rab5-binding CORVET that was suggested to transform into Rab7-binding HOPS. We have previously identified miniCORVET, containing Drosophila Vps8 and three shared core proteins, which are required for endosome maturation upstream of HOPS in highly endocytic cells (Lo˝rincz et al., 2016a). Here, we show that Vps8 overexpression inhibits HOPS-dependent trafficking routes including late endosome maturation, autophagosome-lysosome fusion, crinophagy and lysosome-related organelle formation. Mechanistically, Vps8 overexpression abolishes the late endosomal localization of HOPS-specific Vps41/Lt and prevents HOPS assembly. Proper ratio of Vps8 to Vps41 is thus critical because Vps8 negatively regulates HOPS by outcompeting Vps41. Endosomal recruitment of miniCORVET- or HOPS-specific subunits requires proper complex assembly, and Vps8/miniCORVET is dispensable for autophagy, crinophagy and lysosomal biogenesis. These data together indicate the recruitment of these complexes to target membranes independent of each other in Drosophila, rather than their transformation during *For correspondence: vesicle maturation. [email protected] (PL); DOI: https://doi.org/10.7554/eLife.45631.001 [email protected] (GJ) Competing interests: The authors declare that no competing interests exist. -
Protein Interaction Network of Alternatively Spliced Isoforms from Brain Links Genetic Risk Factors for Autism
ARTICLE Received 24 Aug 2013 | Accepted 14 Mar 2014 | Published 11 Apr 2014 DOI: 10.1038/ncomms4650 OPEN Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism Roser Corominas1,*, Xinping Yang2,3,*, Guan Ning Lin1,*, Shuli Kang1,*, Yun Shen2,3, Lila Ghamsari2,3,w, Martin Broly2,3, Maria Rodriguez2,3, Stanley Tam2,3, Shelly A. Trigg2,3,w, Changyu Fan2,3, Song Yi2,3, Murat Tasan4, Irma Lemmens5, Xingyan Kuang6, Nan Zhao6, Dheeraj Malhotra7, Jacob J. Michaelson7,w, Vladimir Vacic8, Michael A. Calderwood2,3, Frederick P. Roth2,3,4, Jan Tavernier5, Steve Horvath9, Kourosh Salehi-Ashtiani2,3,w, Dmitry Korkin6, Jonathan Sebat7, David E. Hill2,3, Tong Hao2,3, Marc Vidal2,3 & Lilia M. Iakoucheva1 Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases. -
New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology
Cancer Research and Treatment 2003;35(4):304-313 New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology Yong-Wan Kim, Ph.D.1, Min-Je Suh, M.S.1, Jin-Sik Bae, M.S.1, Su Mi Bae, M.S.1, Joo Hee Yoon, M.D.2, Soo Young Hur, M.D.2, Jae Hoon Kim, M.D.2, Duck Young Ro, M.D.2, Joon Mo Lee, M.D.2, Sung Eun Namkoong, M.D.2, Chong Kook Kim, Ph.D.3 and Woong Shick Ahn, M.D.2 1Catholic Research Institutes of Medical Science, 2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul; 3College of Pharmacy, Seoul National University, Seoul, Korea Purpose: This study utilized both mRNA differential significant genes of unknown function affected by the display and the Gene Ontology (GO) analysis to char- HPV-16-derived pathway. The GO analysis suggested that acterize the multiple interactions of a number of genes the cervical cancer cells underwent repression of the with gene expression profiles involved in the HPV-16- cancer-specific cell adhesive properties. Also, genes induced cervical carcinogenesis. belonging to DNA metabolism, such as DNA repair and Materials and Methods: mRNA differential displays, replication, were strongly down-regulated, whereas sig- with HPV-16 positive cervical cancer cell line (SiHa), and nificant increases were shown in the protein degradation normal human keratinocyte cell line (HaCaT) as a con- and synthesis. trol, were used. Each human gene has several biological Conclusion: The GO analysis can overcome the com- functions in the Gene Ontology; therefore, several func- plexity of the gene expression profile of the HPV-16- tions of each gene were chosen to establish a powerful associated pathway, identify several cancer-specific cel- cervical carcinogenesis pathway. -
Cell-Free Fusion of Bacteria-Containing Phagosomes with Endocytic Compartments
Cell-free fusion of bacteria-containing phagosomes with endocytic compartments Ulrike Becken, Andreas Jeschke, Katharina Veltman1, and Albert Haas2 Cell Biology Institute, University of Bonn, Ulrich-Haberland-Strasse 61a, 53121 Bonn, Germany Edited by Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany, and accepted by the Editorial Board October 4, 2010 (received for review June 2, 2010) Uptake of microorganisms by professional phagocytic cells leads to duced fusion of SCPs with lysosomes compared to phagosomes formation of a new subcellular compartment, the phagosome, containing inert particles (10–12), others did not (13). Fusogeni- which matures by sequential fusion with early and late endocytic city of SCPs with other endocytic organelles in macrophages has compartments, resulting in oxidative and nonoxidative killing of been investigated little (10). the enclosed microbe. Few tools are available to study membrane To truly understand the (dys)function of phagosome matura- fusion between phagocytic and late endocytic compartments in tion at a molecular level, the fusion of endocytic with microbe- general and with pathogen-containing phagosomes in particular. containing phagocytic organelles ought to be investigated in We have developed and applied a fluorescence microscopy assay reconstituted systems, yet most published assays used bead- to study fusion of microbe-containing phagosomes with different- containing but not microbe-containing phagosomes (3, 5) and aged endocytic compartments in vitro. This revealed that fusion were limited to fusion of early phagosomes with early endocytic of phagosomes containing nonpathogenic Escherichia coli with organelles (14, 15). Fusion of lysosomes with microbe-containing lysosomes requires Rab7 and SNARE proteins but not organelle phagosomes has been reconstituted only in permeabilized macro- acidification. -
The Mouse Organellar Biogenesis Mutant Buff Results from a Mutation in Vps33a, a Homologue of Yeast Vps33 and Drosophila Carnation
The mouse organellar biogenesis mutant buff results from a mutation in Vps33a, a homologue of yeast vps33 and Drosophila carnation Tamio Suzuki*†‡, Naoki Oiso*†, Rashi Gautam†§, Edward K. Novak§, Jean-Jacques Panthier¶, P. G. Suprabhaʈ, Thomas Vida**, Richard T. Swank§, and Richard A. Spritz*†† *Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, CO 80262; §Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263; ¶Institut National de la Recherche Agronomique, Ecole Nationale Ve´te´ rinaire d’Alfort, 94704 Maisons-Alfort Cedex, France; ʈCenter for Basic Neuroscience, University of Texas Southwestern, Dallas, TX 75390; and **Department of Microbiology and Molecular Genetics, University of Texas Medical School, Houston, TX 77030 Communicated by Theodore T. Puck, Eleanor Roosevelt Institute for Cancer Research, Denver, CO, December 2, 2002 (received for review July 16, 2002) In the mouse, more than 16 loci are associated with mutant bf-mutant Vps33a does not. These results establish murine bf as phenotypes that include defective pigmentation, aberrant target- a murine homologue to the yeast vps33 mutant and suggest ing of lysosomal enzymes, prolonged bleeding, and immunodefi- VPS33A as a candidate gene for some cases of human HPS. ciency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of Materials and Methods these mouse mutants are homologous to the human Hermansky– Mice and Backcross. Mice carrying the spontaneous mutation bf on Pudlak syndrome (HPS), Chediak–Higashi syndrome, and Griscelli the C57BL͞6J strain were obtained from The Jackson Labora- syndrome. We have mapped and positionally cloned one of these tory and were subsequently bred at Roswell Park Cancer Insti- mouse loci, buff (bf), which has a mutant phenotype similar to that tute. -
A Minimum-Labeling Approach for Reconstructing Protein Networks Across Multiple Conditions
A Minimum-Labeling Approach for Reconstructing Protein Networks across Multiple Conditions Arnon Mazza1, Irit Gat-Viks2, Hesso Farhan3, and Roded Sharan1 1 Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel. Email: [email protected]. 2 Dept. of Cell Research and Immunology, Tel Aviv University, Tel Aviv 69978, Israel. 3 Biotechnology Institute Thurgau, University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland. Abstract. The sheer amounts of biological data that are generated in recent years have driven the development of network analysis tools to fa- cilitate the interpretation and representation of these data. A fundamen- tal challenge in this domain is the reconstruction of a protein-protein sub- network that underlies a process of interest from a genome-wide screen of associated genes. Despite intense work in this area, current algorith- mic approaches are largely limited to analyzing a single screen and are, thus, unable to account for information on condition-specific genes, or reveal the dynamics (over time or condition) of the process in question. Here we propose a novel formulation for network reconstruction from multiple-condition data and devise an efficient integer program solution for it. We apply our algorithm to analyze the response to influenza in- fection in humans over time as well as to analyze a pair of ER export related screens in humans. By comparing to an extant, single-condition tool we demonstrate the power of our new approach in integrating data from multiple conditions in a compact and coherent manner, capturing the dynamics of the underlying processes. 1 Introduction With the increasing availability of high-throughput data, network biol- arXiv:1307.7803v1 [q-bio.QM] 30 Jul 2013 ogy has become the method of choice for filtering, interpreting and rep- resenting these data. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Supplementary Materials
1 Supplementary Materials: Supplemental Figure 1. Gene expression profiles of kidneys in the Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice. (A) A heat map of microarray data show the genes that significantly changed up to 2 fold compared between Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice (N=4 mice per group; p<0.05). Data show in log2 (sample/wild-type). 2 Supplemental Figure 2. Sting signaling is essential for immuno-phenotypes of the Fcgr2b-/-lupus mice. (A-C) Flow cytometry analysis of splenocytes isolated from wild-type, Fcgr2b-/- and Fcgr2b-/-. Stinggt/gt mice at the age of 6-7 months (N= 13-14 per group). Data shown in the percentage of (A) CD4+ ICOS+ cells, (B) B220+ I-Ab+ cells and (C) CD138+ cells. Data show as mean ± SEM (*p < 0.05, **p<0.01 and ***p<0.001). 3 Supplemental Figure 3. Phenotypes of Sting activated dendritic cells. (A) Representative of western blot analysis from immunoprecipitation with Sting of Fcgr2b-/- mice (N= 4). The band was shown in STING protein of activated BMDC with DMXAA at 0, 3 and 6 hr. and phosphorylation of STING at Ser357. (B) Mass spectra of phosphorylation of STING at Ser357 of activated BMDC from Fcgr2b-/- mice after stimulated with DMXAA for 3 hour and followed by immunoprecipitation with STING. (C) Sting-activated BMDC were co-cultured with LYN inhibitor PP2 and analyzed by flow cytometry, which showed the mean fluorescence intensity (MFI) of IAb expressing DC (N = 3 mice per group). 4 Supplemental Table 1. Lists of up and down of regulated proteins Accession No. -
The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity
The schizophrenia risk gene product miR-137 alters presynaptic plasticity The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Siegert, S., J. Seo, E. J. Kwon, A. Rudenko, S. Cho, W. Wang, Z. Flood, et al. 2015. “The schizophrenia risk gene product miR-137 alters presynaptic plasticity.” Nature neuroscience 18 (7): 1008-1016. doi:10.1038/nn.4023. http://dx.doi.org/10.1038/nn.4023. Published Version doi:10.1038/nn.4023 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983896 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author Manuscript Author ManuscriptNat Neurosci Author Manuscript. Author manuscript; Author Manuscript available in PMC 2016 January 01. Published in final edited form as: Nat Neurosci. 2015 July ; 18(7): 1008–1016. doi:10.1038/nn.4023. The schizophrenia risk gene product miR-137 alters presynaptic plasticity Sandra Siegert1,2, Jinsoo Seo1,2,*, Ester J. Kwon1,2,*, Andrii Rudenko1,2,*, Sukhee Cho1,2, Wenyuan Wang1,2, Zachary Flood1,2, Anthony J. Martorell1,2, Maria Ericsson4, Alison E. Mungenast1,2, and Li-Huei Tsai1,2,3,5 1Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA 2Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA 3Broad Institute of MIT and Harvard, Cambridge, MA, USA 4Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA Abstract Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genome- wide significance level. -
Mig-6 Controls EGFR Trafficking and Suppresses Gliomagenesis
Mig-6 controls EGFR trafficking and suppresses gliomagenesis Haoqiang Yinga,1, Hongwu Zhenga,1, Kenneth Scotta, Ruprecht Wiedemeyera, Haiyan Yana, Carol Lima, Joseph Huanga, Sabin Dhakala, Elena Ivanovab, Yonghong Xiaob,HaileiZhangb,JianHua, Jayne M. Stommela, Michelle A. Leea, An-Jou Chena, Ji-Hye Paika,OresteSegattoc, Cameron Brennand,e, Lisa A. Elferinkf,Y.AlanWanga,b, Lynda China,b,g, and Ronald A. DePinhoa,b,h,2 aDepartment of Medical Oncology, bBelfer Institute for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115; cLaboratory of Immunology, Istituto Regina Elena, Rome 00158, Italy; dHuman Oncology and Pathogenesis Program and eDepartment of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; fDepartment of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555; gDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and hDepartment of Medicine and Genetics, Harvard Medical School, Boston, MA 02115 Edited* by Webster K. Cavenee, Ludwig Institute, University of California, La Jolla, CA, and approved March 8, 2010 (received for review December 23, 2009) Glioblastoma multiforme (GBM) is the most common and lethal structural aberrations that serve as a key pathological driving primary brain cancer that is driven by aberrant signaling of growth force for tumor progression and many of them remain to be factor receptors, particularly the epidermal growth factor receptor characterized (6, 7). GBM possesses a highly rearranged genome (EGFR). EGFR signaling is tightly regulated by receptor endocytosis and high-resolution genome analysis has uncovered myriad and lysosome-mediated degradation, although the molecular somatic alterations on the genomic and epigenetic levels (2, 3).