DOCSLIB.ORG

RAB-GAP Immunity Signaling by the Tbc1d23 Spatiotemporal Inhibition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
RAB-GAP Immunity Signaling by the Tbc1d23 Spatiotemporal Inhibition Downloaded from http://www.jimmunol.org/ by guest on September 27, 2021 is online at: average * The Journal of Immunology , 17 of which you can access for free at: 2012; 188:2905-2913; Prepublished online 6 from submission to initial decision 4 weeks from acceptance to publication February 2012; doi: 10.4049/jimmunol.1102595 http://www.jimmunol.org/content/188/6/2905 Spatiotemporal Inhibition of Innate Immunity Signaling by the Tbc1d23 RAB-GAP Lesly De Arras, Ivana V. Yang, Brad Lackford, David W. H. Riches, Rytis Prekeris, Jonathan H. Freedman, David A. Schwartz and Scott Alper J Immunol cites 58 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/02/06/jimmunol.110259 5.DC1 This article http://www.jimmunol.org/content/188/6/2905.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 27, 2021. The Journal of Immunology Spatiotemporal Inhibition of Innate Immunity Signaling by the Tbc1d23 RAB-GAP Lesly De Arras,*,† Ivana V. Yang,†,‡ Brad Lackford,x David W. H. Riches,*,‡,{ Rytis Prekeris,‖ Jonathan H. Freedman,# David A. Schwartz,†,‡ and Scott Alper*,† We previously identified Tbc1d23 as a candidate novel regulator of innate immunity using comparative genomics RNA interfer- ence screens in Caenorhabditis elegans and mouse macrophages. Using Tbc1d23 knockout mice and macrophages engineered to overexpress Tbc1d23, we now show that Tbc1d23 is a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin-signaling pathways. Tbc1d23 likely acts downstream of the TLR-signaling adaptors MyD88 and Trif and upstream of the transcription factor XBP1. Importantly, like XBP1, Tbc1d23 affects the maintenance, but not the initiation, of inflammatory cytokine production induced by LPS. Tbc1d23 acts as a RAB-GAP to regulate innate immunity signaling. Thus, Tbc1d23 exerts its inhibitory effect on innate immunity signaling in a spatiotemporal fashion. The identification of a novel Downloaded from spatiotemporal regulator of innate immunity signaling validates the comparative genomics approach for innate immunity gene discovery. The Journal of Immunology, 2012, 188: 2905–2913. he innate immune response plays a critical role in fighting including LPS. In contrast, overexpression of Tbc1d23 in mac- infection (1). However, if this response is activated too rophages inhibits the response to numerous PAMPs. Tbc1d23 is T strongly or becomes chronic, this can cause or contribute a general inhibitor of innate immunity signaling, affecting TLR http://www.jimmunol.org/ to a variety of diseases, including sepsis, Crohn’s disease, ath- and dectin signaling. The response to LPS is initiated by TLR4, erosclerosis, and cancer (2–5). We previously used comparative which signals through MyD88 and Trif to activate NF-kB, IRF3, genomics RNA interference screens in Caenorhabditis elegans and the MAPKs p38, ERK, and JNK (11–13). This has a variety of and mouse macrophages to identify novel regulators of innate effects, including production of inflammatory cytokines. We show immunity (6). Such regulators are potential targets for the devel- that Tbc1d23 likely acts downstream of MyD88 and Trif and opment of novel therapeutic and diagnostic options (3, 7–10). In upstream of the XBP1 transcription factor to inhibit TLR signal- these comparative genomics screens, we identified Tbc1d23 as ing. a novel conserved regulator of innate immunity. Nematodes har- Importantly, we find that Tbc1d23 inhibits the innate immune boring a mutation in tbc-1 (the C. elegans Tbc1d23 ortholog) have response in a spatiotemporal fashion. In contrast to the substantial by guest on September 27, 2021 altered antimicrobial gene expression and diminished survival in body of work investigating the initiation of inflammation, much the presence of pathogenic, but not nonpathogenic, bacteria (6). less is known about the maintenance of this response (14–16). We have now generated a murine knockout of Tbc1d23. In this Tbc1d23 does not alter initial activation events but instead affects article, we show that Tbc1d232/2 mice and macrophages exhibit maintenance of inflammatory gene expression several hours after increased inflammatory cytokine production when challenged LPS challenge. There has been a substantial effort to identify the with different pathogen-associated molecular patterns (PAMPs), signaling pathways that regulate innate immunity (11, 13). In contrast, the study of how the subcellular transport machinery affects innate immunity signaling is a younger field that has re- *Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, CO 80206; †Center for Genes, Environment and Health, National cently gained much attention (17). Tbc1d23 contains two con- Jewish Health, Denver, CO 80206; ‡Department of Medicine, University of Colorado, x served domains: the Tbc domain, which functions as a RAB Aurora, CO 80045; Laboratory of Molecular Carcinogenesis, National Institute of GTPase-activating protein (RAB-GAP) domain (18–20), and a Environmental Health Sciences, National Institutes of Health, Durham, NC 27709; {Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, rhodanese superfamily domain (21, 22). We show that Tbc1d23 ‖ CO 80206; Department of Cell and Developmental Biology, University of Colorado, functions as a RAB-GAP to inhibit innate immunity signaling. Aurora, CO 80045; and #Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC 27709 Materials and Methods Received for publication September 9, 2011. Accepted for publication January 13, Generation and phenotyping of Tbc1d23 knockout mice 2012. Mouse experiments were approved by the National Jewish Health Insti- This work was supported by R21ES019256 from the National Institute of Environ- tutional Animal Care and Use Committee (protocol no. AS2801-06-12). mental Health Sciences and the Intramural Research Programs of the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences Every effort was made to ensure that discomfort, distress, or pained in- (Z01ES102045 and Z01ES101946). jury to the animals was limited to that which was unavoidable in the conduct of scientifically sound research. Tbc1d23 knockout mice were generated by The array data presented in this article have been deposited in the Gene Expression injecting mouse embryonic stem cell line BA0556 (International Gene Trap Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE30840. Consortium) into blastocysts from C57BL/6 mice. The resulting Tbc1d23 gene-trapped mice were outcrossed six times to C57BL/6 (JAX). The Address correspondence and reprint requests to Dr. Scott Alper, National Jewish BA0556 gene trap was inserted in the first intron of Tbc1d23. By sequencing Health, 1400 Jackson Street, Denver, CO 80206. E-mail address: [email protected] PCR products within this intron, we determined that the gene trap was 2893 The online version of this article contains supplemental material. bp past the first base pair in exon 1 of Tbc1d23. Mice were genotyped by Abbreviations used in this article: BMDM, bone marrow-derived macrophage; CAT, PCR amplification of genomic DNA using a mix of three primers: oSA512, chloramphenicol acetyltransferase; ER, endoplasmic reticulum; PAMP, pathogen- oSA513, and oSA516 (Supplemental Table I). This generated a 313-bp associated molecular pattern; qPCR, quantitative PCR. product for the wild-type chromosome and a 221-bp product for the mutant. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102595 2906 Tbc1d23 INHIBITS INNATE IMMUNITY SIGNALING Tbc1d232/2 mice produced little or no Tbc1d23 RNA, as evidenced by implementation in Partek (St. Louis, MO), and differentially expressed quantitative PCR (qPCR) using three primer sets (Supplemental Table I) genes were identified using two-factor ANOVA in MultiExperiment Viewer that span the Tbc1d23 gene: primers that span exons 1 and 2 (2.5% of (http://www.tm4.org) (30). Differentially expressed genes in LPS-treated wild-type in spleen, 5.7% of wild-type in bone marrow-derived macro- cells compared with untreated cells in the CMV–myc–Tbc1d23 line com- phages [BMDMs]), primers that span exons 2 and 3 (2.8% spleen, 0.9% pared with the control CMV-CAT cell line were identified as interaction BMDMs), and primers that span exons 13 and 14 (3.9% spleen, 5.3% genes from the two-factor ANOVA analysis. Genes with Bonferroni- BMDMs). All experiments compared Tbc1d232/2 male mice with their corrected p values , 0.05 (corresponding to raw p , 1 3 1026) were age-matched (6–10-wk-old) wild-type littermates generated from hetero- considered statistically significant. The analysis was done separately for zygous 3 heterozygous matings. different time points. Pathway analysis of significant genes was
Load more

Recommended publications
  • Genome-Wide Approach to Identify Risk Factors for Therapy-Related Myeloid Leukemia
    Leukemia (2006) 20, 239–246 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu ORIGINAL ARTICLE Genome-wide approach to identify risk factors for therapy-related myeloid leukemia A Bogni1, C Cheng2, W Liu2, W Yang1, J Pfeffer1, S Mukatira3, D French1, JR Downing4, C-H Pui4,5,6 and MV Relling1,6 1Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN, USA; 2Department of Biostatistics, The University of Tennessee, Memphis, TN, USA; 3Hartwell Center, The University of Tennessee, Memphis, TN, USA; 4Department of Pathology, The University of Tennessee, Memphis, TN, USA; 5Department of Hematology/Oncology St Jude Children’s Research Hospital, The University of Tennessee, Memphis, TN, USA; and 6Colleges of Medicine and Pharmacy, The University of Tennessee, Memphis, TN, USA Using a target gene approach, only a few host genetic risk therapy increases, the importance of identifying host factors for factors for treatment-related myeloid leukemia (t-ML) have been secondary neoplasms increases. defined. Gene expression microarrays allow for a more 4 genome-wide approach to assess possible genetic risk factors Because DNA microarrays interrogate multiple ( 10 000) for t-ML. We assessed gene expression profiles (n ¼ 12 625 genes in one experiment, they allow for a ‘genome-wide’ probe sets) in diagnostic acute lymphoblastic leukemic cells assessment of genes that may predispose to leukemogenesis. from 228 children treated on protocols that included leukemo- DNA microarray analysis of gene expression has been used to genic agents such as etoposide, 13 of whom developed t-ML. identify distinct expression profiles that are characteristic of Expression of 68 probes, corresponding to 63 genes, was different leukemia subtypes.13,14 Studies using this method have significantly related to risk of t-ML.
    [Show full text]
  • Supporting Online Material
    1 2 3 4 5 6 7 Supplementary Information for 8 9 Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic 10 retinopathy 11 12 *Samuel A. Mills, *Andrew I. Jobling, *Michael A. Dixon, Bang V. Bui, Kirstan A. Vessey, Joanna A. Phipps, 13 Ursula Greferath, Gene Venables, Vickie H.Y. Wong, Connie H.Y. Wong, Zheng He, Flora Hui, James C. 14 Young, Josh Tonc, Elena Ivanova, Botir T. Sagdullaev, Erica L. Fletcher 15 * Joint first authors 16 17 Corresponding author: 18 Prof. Erica L. Fletcher. Department of Anatomy & Neuroscience. The University of Melbourne, Grattan St, 19 Parkville 3010, Victoria, Australia. 20 Email: [email protected] ; Tel: +61-3-8344-3218; Fax: +61-3-9347-5219 21 22 This PDF file includes: 23 24 Supplementary text 25 Figures S1 to S10 26 Tables S1 to S7 27 Legends for Movies S1 to S2 28 SI References 29 30 Other supplementary materials for this manuscript include the following: 31 32 Movies S1 to S2 33 34 35 36 1 1 Supplementary Information Text 2 Materials and Methods 3 Microglial process movement on retinal vessels 4 Dark agouti rats were anaesthetized, injected intraperitoneally with rhodamine B (Sigma-Aldrich) to label blood 5 vessels and retinal explants established as described in the main text. Retinal microglia were labelled with Iba-1 6 and imaging performed on an inverted confocal microscope (Leica SP5). Baseline images were taken for 10 7 minutes, followed by the addition of PBS (10 minutes) and then either fractalkine or fractalkine + candesartan 8 (10 minutes) using concentrations outlined in the main text.
    [Show full text]
  • 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.
    [Show full text]
  • Plasma Omentin Levels Are Inversely Associated with Atherosclerosis In
    Nishimura et al. Cardiovasc Diabetol (2019) 18:167 https://doi.org/10.1186/s12933-019-0973-3 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study Masami Nishimura1, Tomoaki Morioka1* , Mariko Hayashi1, Yoshinori Kakutani1, Yuko Yamazaki1, Masafumi Kurajoh1, Katsuhito Mori2, Shinya Fukumoto3, Atsushi Shioi4,5, Tetsuo Shoji4,5, Masaaki Inaba1,5 and Masanori Emoto1 Abstract Background: Omentin and adiponectin are among the anti-infammatory and anti-atherogenic adipokines that have potentially benefcial efects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and exam- ined the association between omentin and atherosclerosis in those patients. Methods: The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratifed according to the median value of plasma adiponectin. Results: In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low- adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors.
    [Show full text]
  • Human Retinoic Acid Signaling
    RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Human Retinoic Acid Signaling Cat. no. 330231 PAHS-180Z For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Human Retinoic Acid Pathway RT² Profiler PCR Array profiles the expression of 84 key genes involved in retinoic acid signaling. Retinoic acid (RA) is the primary functional derivative of vitamin A (retinol) and its activity is implicated in many aspects of vertebrate development and homeostasis, while disruptions in this pathway cause developmental abnormalities and disrupt function in adipose, cardiac, nervous, reproductive, and integumentary tissues, among others. RA acts primarily by binding a family of nuclear receptors (the retinoic acid receptors alpha, beta, and gamma) that then heterodimerize with their partners (the retinoid X receptors alpha, beta, and gamma) and alter transcription.
    [Show full text]
  • (Title of the Thesis)*
    THE PHYSIOLOGICAL ACTIONS OF ADIPONECTIN IN CENTRAL AUTONOMIC NUCLEI: IMPLICATIONS FOR THE INTEGRATIVE CONTROL OF ENERGY HOMEOSTASIS by Ted Donald Hoyda A thesis submitted to the Department of Physiology In conformity with the requirements for the degree of Doctor of Philosophy Queen‟s University Kingston, Ontario, Canada (September, 2009) Copyright © Ted Donald Hoyda, 2009 ABSTRACT Adiponectin regulates feeding behavior, energy expenditure and autonomic function through the activation of two receptors present in nuclei throughout the central nervous system, however much remains unknown about the mechanisms mediating these effects. Here I investigate the actions of adiponectin in autonomic centers of the hypothalamus (the paraventricular nucleus) and brainstem (the nucleus of the solitary tract) through examining molecular, electrical, hormonal and physiological consequences of peptidergic signalling. RT-PCR and in situ hybridization experiments demonstrate the presence of AdipoR1 and AdipoR2 mRNA in the paraventricular nucleus. Investigation of the electrical consequences following receptor activation in the paraventricular nucleus indicates that magnocellular-oxytocin cells are homogeneously inhibited while magnocellular-vasopressin neurons display mixed responses. Single cell RT-PCR analysis shows oxytocin neurons express both receptors while vasopressin neurons express either both receptors or one receptor. Co-expressing oxytocin and vasopressin neurons express neither receptor and are not affected by adiponectin. Median eminence projecting corticotropin releasing hormone neurons, brainstem projecting oxytocin neurons, and thyrotropin releasing hormone neurons are all depolarized by adiponectin. Plasma adrenocorticotropin hormone concentration is increased following intracerebroventricular injections of adiponectin. I demonstrate that the nucleus of the solitary tract, the primary cardiovascular regulation site of the medulla, expresses mRNA for AdipoR1 and AdipoR2 and mediates adiponectin induced hypotension.
    [Show full text]
  • Uncovering Ubiquitin and Ubiquitin-Like Signaling Networks Alfred C
    REVIEW pubs.acs.org/CR Uncovering Ubiquitin and Ubiquitin-like Signaling Networks Alfred C. O. Vertegaal* Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands CONTENTS 8. Crosstalk between Post-Translational Modifications 7934 1. Introduction 7923 8.1. Crosstalk between Phosphorylation and 1.1. Ubiquitin and Ubiquitin-like Proteins 7924 Ubiquitylation 7934 1.2. Quantitative Proteomics 7924 8.2. Phosphorylation-Dependent SUMOylation 7935 8.3. Competition between Different Lysine 1.3. Setting the Scenery: Mass Spectrometry Modifications 7935 Based Investigation of Phosphorylation 8.4. Crosstalk between SUMOylation and the and Acetylation 7925 UbiquitinÀProteasome System 7935 2. Ubiquitin and Ubiquitin-like Protein Purification 9. Conclusions and Future Perspectives 7935 Approaches 7925 Author Information 7935 2.1. Epitope-Tagged Ubiquitin and Ubiquitin-like Biography 7935 Proteins 7925 Acknowledgment 7936 2.2. Traps Based on Ubiquitin- and Ubiquitin-like References 7936 Binding Domains 7926 2.3. Antibody-Based Purification of Ubiquitin and Ubiquitin-like Proteins 7926 1. INTRODUCTION 2.4. Challenges and Pitfalls 7926 Proteomes are significantly more complex than genomes 2.5. Summary 7926 and transcriptomes due to protein processing and extensive 3. Ubiquitin Proteomics 7927 post-translational modification (PTM) of proteins. Hundreds ff fi 3.1. Proteomic Studies Employing Tagged of di erent modi cations exist. Release 66 of the RESID database1 (http://www.ebi.ac.uk/RESID/) contains 559 dif- Ubiquitin 7927 ferent modifications, including small chemical modifications 3.2. Ubiquitin Binding Domains 7927 such as phosphorylation, acetylation, and methylation and mod- 3.3. Anti-Ubiquitin Antibodies 7927 ification by small proteins, including ubiquitin and ubiquitin- 3.4.
    [Show full text]
  • Α Are Regulated by Heat Shock Protein 90
    The Levels of Retinoic Acid-Inducible Gene I Are Regulated by Heat Shock Protein 90- α Tomoh Matsumiya, Tadaatsu Imaizumi, Hidemi Yoshida, Kei Satoh, Matthew K. Topham and Diana M. Stafforini This information is current as of October 2, 2021. J Immunol 2009; 182:2717-2725; ; doi: 10.4049/jimmunol.0802933 http://www.jimmunol.org/content/182/5/2717 Downloaded from References This article cites 44 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/182/5/2717.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Levels of Retinoic Acid-Inducible Gene I Are Regulated by Heat Shock Protein 90-␣1 Tomoh Matsumiya,*‡ Tadaatsu Imaizumi,‡ Hidemi Yoshida,‡ Kei Satoh,‡ Matthew K. Topham,*† and Diana M. Stafforini2*† Retinoic acid-inducible gene I (RIG-I) is an intracellular pattern recognition receptor that plays important roles during innate immune responses to viral dsRNAs.
    [Show full text]
  • NIH Public Access Author Manuscript Rev Endocr Metab Disord
    NIH Public Access Author Manuscript Rev Endocr Metab Disord. Author manuscript; available in PMC 2014 September 03. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Rev Endocr Metab Disord. 2014 June ; 15(2): 137–147. doi:10.1007/s11154-013-9280-6. ADIPONECTIN SIGNALING IN THE LIVER Terry P. Combs1,2,3 and Errol B. Marliss2 1Department of Medicine, University of North Carolina at Chapel Hill 2Crabtree Nutrition Laboratories, Department of Medicine, McGill University Abstract High glucose production contributes to fed and fasted hyperglycemia in Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). The breakdown of the adiponectin signaling pathway in T1D and the reduction of circulating adiponectin in T2D contribute to this abnormal increase in glucose production. Sufficient amounts of insulin could compensate for the loss of adiponectin signaling in T1D and T2D and reduce hyperglycemia. However, the combination of low adiponectin signaling and high insulin resembles an insulin resistance state associated with cardiovascular disease and decreased life expectancy. Future development of medications that correct the deficiency of adiponectin signaling in the liver could restore the metabolic balance in T1D and T2D and reduce the need for insulin. This article reviews the adiponectin signaling pathway in the liver through T- cadherin, AdipoR1, AdipoR2, AMPK, ceramidase activity, APPL1 and the recently discovered Suppressor Of Glucose from Autophagy (SOGA). 1. Liver contribution to circulating glucose The liver releases glucose ensuring sufficient amounts of this essential fuel are always available in the circulation for other tissues. Endocrine and neural mechanisms stimulate the liver during fasting, exercise and pregnancy to meet the increased demand for glucose.
    [Show full text]
  • Global Mef2 Target Gene Analysis in Skeletal and Cardiac Muscle
    GLOBAL MEF2 TARGET GENE ANALYSIS IN SKELETAL AND CARDIAC MUSCLE STEPHANIE ELIZABETH WALES A DISSERTATION SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN BIOLOGY YORK UNIVERSITY TORONTO, ONTARIO FEBRUARY 2016 © Stephanie Wales 2016 ABSTRACT A loss of muscle mass or function occurs in many genetic and acquired pathologies such as heart disease, sarcopenia and cachexia which are predominantly found among the rapidly increasing elderly population. Developing effective treatments relies on understanding the genetic networks that control these disease pathways. Transcription factors occupy an essential position as regulators of gene expression. Myocyte enhancer factor 2 (MEF2) is an important transcription factor in striated muscle development in the embryo, skeletal muscle maintenance in the adult and cardiomyocyte survival and hypertrophy in the progression to heart failure. We sought to identify common MEF2 target genes in these two types of striated muscles using chromatin immunoprecipitation and next generation sequencing (ChIP-seq) and transcriptome profiling (RNA-seq). Using a cell culture model of skeletal muscle (C2C12) and primary cardiomyocytes we found 294 common MEF2A binding sites within both cell types. Individually MEF2A was recruited to approximately 2700 and 1600 DNA sequences in skeletal and cardiac muscle, respectively. Two genes were chosen for further study: DUSP6 and Hspb7. DUSP6, an ERK1/2 specific phosphatase, was negatively regulated by MEF2 in a p38MAPK dependent manner in striated muscle. Furthermore siRNA mediated gene silencing showed that MEF2D in particular was responsible for repressing DUSP6 during C2C12 myoblast differentiation. Using a p38 pharmacological inhibitor (SB 203580) we observed that MEF2D must be phosphorylated by p38 to repress DUSP6.
    [Show full text]
  • Quantigene Flowrna Probe Sets Currently Available
    QuantiGene FlowRNA Probe Sets Currently Available Accession No. Species Symbol Gene Name Catalog No. NM_003452 Human ZNF189 zinc finger protein 189 VA1-10009 NM_000057 Human BLM Bloom syndrome VA1-10010 NM_005269 Human GLI glioma-associated oncogene homolog (zinc finger protein) VA1-10011 NM_002614 Human PDZK1 PDZ domain containing 1 VA1-10015 NM_003225 Human TFF1 Trefoil factor 1 (breast cancer, estrogen-inducible sequence expressed in) VA1-10016 NM_002276 Human KRT19 keratin 19 VA1-10022 NM_002659 Human PLAUR plasminogen activator, urokinase receptor VA1-10025 NM_017669 Human ERCC6L excision repair cross-complementing rodent repair deficiency, complementation group 6-like VA1-10029 NM_017699 Human SIDT1 SID1 transmembrane family, member 1 VA1-10032 NM_000077 Human CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) VA1-10040 NM_003150 Human STAT3 signal transducer and activator of transcripton 3 (acute-phase response factor) VA1-10046 NM_004707 Human ATG12 ATG12 autophagy related 12 homolog (S. cerevisiae) VA1-10047 NM_000737 Human CGB chorionic gonadotropin, beta polypeptide VA1-10048 NM_001017420 Human ESCO2 establishment of cohesion 1 homolog 2 (S. cerevisiae) VA1-10050 NM_197978 Human HEMGN hemogen VA1-10051 NM_001738 Human CA1 Carbonic anhydrase I VA1-10052 NM_000184 Human HBG2 Hemoglobin, gamma G VA1-10053 NM_005330 Human HBE1 Hemoglobin, epsilon 1 VA1-10054 NR_003367 Human PVT1 Pvt1 oncogene homolog (mouse) VA1-10061 NM_000454 Human SOD1 Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]