Structural Insights Into Substrate Recognition by the SOCS2 E3 Ubiquitin Ligase
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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 Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic
Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int. -
NOD1 Modulates IL-10 Signalling in Human Dendritic Cells Theresa Neuper1, Kornelia Ellwanger2, Harald Schwarz1, Thomas A
www.nature.com/scientificreports OPEN NOD1 modulates IL-10 signalling in human dendritic cells Theresa Neuper1, Kornelia Ellwanger2, Harald Schwarz1, Thomas A. Kufer 2, Albert Duschl 1 & Jutta Horejs-Hoeck 1 Received: 17 November 2016 NOD1 belongs to the family of NOD-like receptors, which is a group of well-characterised, cytosolic Accepted: 8 March 2017 pattern-recognition receptors. The best-studied function of NOD-like receptors is their role in Published: xx xx xxxx generating immediate pro-inflammatory and antimicrobial responses by detecting specific bacterial peptidoglycans or by responding to cellular stress and danger-associated molecules. The present study describes a regulatory, peptidoglycan-independent function of NOD1 in anti-inflammatory immune responses. We report that, in human dendritic cells, NOD1 balances IL-10-induced STAT1 and STAT3 activation by a SOCS2-dependent mechanism, thereby suppressing the tolerogenic dendritic cell phenotype. Based on these findings, we propose that NOD1 contributes to inflammation not only by promoting pro-inflammatory processes, but also by suppressing anti-inflammatory pathways. NOD-like receptors (NLRs) comprise a family of cytosolic pattern recognition receptors (PRRs) that serves as a first line of defence against invading pathogens. The human NLR family contains 22 members that are structur- ally conserved. NLRs possess a leucine-rich repeat (LRR) domain for ligand sensing, a NOD domain that facili- tates self-oligomerisation upon activation, and an effector domain that mediates downstream signalling. NOD1 and NOD2, the two best-characterised NLRs, recognise specific fragments of bacterial peptidoglycan1, 2. Ligand sensing leads to NF-κB activation and mitogen-activated protein kinase (MAPK)-signalling which results in the production of pro-inflammatory cytokines and chemokines3–6. -
Expression of SOCS1 and SOCS3 Genes Is Differentially Regulated in Breast Cancer Cells in Response to Proinflammatory Cytokine and Growth Factor Signals
Oncogene (2007) 26, 1941–1948 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals MK Evans1, C-R Yu2, A Lohani1, RM Mahdi2, X Liu2, AR Trzeciak1 and CE Egwuagu2 1Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA and 2Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA DNA-hypermethylation of SOCS genes in breast, ova- Keywords: breast-cancer cells; SOCS; breast cancer; STAT; rian, squamous cell and hepatocellular carcinoma has led BRCA1; DNA hypermethylation; interferon to speculation that silencing of SOCS1 and SOCS3 genes might promote oncogenic transformation of epithelial tissues. To examine whether transcriptional silencing of SOCS genes is a common feature of human carcinoma, we have investigated regulation of SOCS genes expression by Introduction IFNc, IGF-1 and ionizing radiation, in a normal human mammary epithelial cell line (AG11134), two breast- Development of the mammary gland is regulated by cancer cell lines (MCF-7, HCC1937) and three prostate factors that coordinate proliferation, differentiation, cancer cell lines. Compared to normal breast cells, we maturation and apoptosis of mammary epithelial cells. observe a high level constitutive expression of SOCS2, Exquisite control of the initiation, strength and duration SOCS3, SOCS5, SOCS6, SOCS7, CIS and/or SOCS1 of signals from the diverse array of cytokines and genes in the human cancer cells. In MCF-7 and HCC1937 growth factors in mammalian breast is essential to the breast-cancer cells, transcription of SOCS1 is dramati- timely initiation of the menstrual cycle, lactation or cally up-regulated by IFNc and/or ionizing-radiation breast lobule involution (Medina, 2005). -
The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia
cancers Review The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia Esra’a Keewan 1,2 and Ksenia Matlawska-Wasowska 1,2,* 1 Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; [email protected] 2 Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA * Correspondence: [email protected]; Tel.: +1-505-272-6177 Simple Summary: The suppressors of cytokine signaling (SOCS) are known cytokine-inducible negative regulators of JAK/STAT and other cell signaling pathways. Deregulation of SOCS expression is linked to various tumor types and inflammatory diseases. While SOCS play a crucial role in the regulation of immune cell function, their roles in hematological malignancies have not been elucidated thus far. In this review, we summarize the current knowledge on the roles of SOCS in leukemia development and progression. We delineate the paradoxical activities of SOCS in different leukemia types and the regulatory mechanisms underlying SOCS deregulation in leukemia. Lastly, we discuss the possible implications of SOCS deregulation for leukemia diagnosis and prognosis. This paper provides new insights into the roles of SOCS in the pathobiology of leukemia and leukemia research. Abstract: Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular Citation: Keewan, E.; signaling cascades in the target cell that bring about a wide range of cellular responses, including Matlawska-Wasowska, K. The induction of cell proliferation, migration, differentiation, and apoptosis. -
Potential Implications for SOCS in Chronic Wound Healing
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 38: 1349-1358, 2016 Expression of the SOCS family in human chronic wound tissues: Potential implications for SOCS in chronic wound healing YI FENG1, ANDREW J. SANDERS1, FIONA RUGE1,2, CERI-ANN MORRIS2, KEITH G. HARDING2 and WEN G. JIANG1 1Cardiff China Medical Research Collaborative and 2Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, UK Received April 12, 2016; Accepted August 2, 2016 DOI: 10.3892/ijmm.2016.2733 Abstract. Cytokines play important roles in the wound an imbalance between proteinases and their inhibitors, and healing process through various signalling pathways. The the presence of senescent cells is of importance in chronic JAK-STAT pathway is utilised by most cytokines for signal wounds (1). A variety of treatments, such as dressings, appli- transduction and is regulated by a variety of molecules, cation of topical growth factors, autologous skin grafting and including suppressor of cytokine signalling (SOCS) proteins. bioengineered skin equivalents have been applied to deal SOCS are associated with inflammatory diseases and have with certain types of chronic wounds in addition to the basic an impact on cytokines, growth factors and key cell types treatments (1). However, the specific mechanisms of each trea- involved in the wound-healing process. SOCS, a negative ment remain unclear and are under investigation. Therefore, regulator of cytokine signalling, may hold the potential more insight into the mechanisms responsible are required to regulate cytokine-induced signalling in the chronic to gain a better understanding of the wound-healing process. wound-healing process. Wound edge tissues were collected Further clarification of this complex system may contribute to from chronic venous leg ulcer patients and classified as non- the emergence of a prognositc marker to predict the healing healing and healing wounds. -
SOCS7 Antibody Cat
SOCS7 Antibody Cat. No.: 58-953 SOCS7 Antibody Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human HOMOLOGY: Predicted species reactivity based on immunogen sequence: Mouse This SOCS7 antibody is generated from rabbits immunized with a KLH conjugated IMMUNOGEN: synthetic peptide between 458-486 amino acids from the C-terminal region of human SOCS7. TESTED APPLICATIONS: WB APPLICATIONS: For WB starting dilution is: 1:1000 PREDICTED MOLECULAR 63 kDa WEIGHT: Properties This antibody is purified through a protein A column, followed by peptide affinity PURIFICATION: purification. CLONALITY: Polyclonal ISOTYPE: Rabbit Ig October 2, 2021 1 https://www.prosci-inc.com/socs7-antibody-58-953.html CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: Supplied in PBS with 0.09% (W/V) sodium azide. CONCENTRATION: batch dependent Store at 4˚C for three months and -20˚C, stable for up to one year. As with all antibodies STORAGE CONDITIONS: care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: SOCS7 Suppressor of cytokine signaling 7, SOCS-7, Nck, Ash and phospholipase C gamma-binding ALTERNATE NAMES: protein, Nck-associated protein 4, NAP-4, SOCS7, NAP4, SOCS6 ACCESSION NO.: O14512 GENE ID: 30837 USER NOTE: Optimal dilutions for each application to be determined by the researcher. Background and References Regulates signaling cascades probably through protein ubiquitination and/or sequestration. Functions in insulin signaling and glucose homeostasis through IRS1 ubiquitination and subsequent proteasomal degradation. Inhibits also prolactin, growth BACKGROUND: hormone and leptin signaling by preventing STAT3 and STAT5 activation, sequestering them in the cytoplasm and reducing their binding to DNA. -
Negative Regulation of Cytokine Signaling in Immunity
Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Negative Regulation of Cytokine Signaling in Immunity Akihiko Yoshimura, Minako Ito, Shunsuke Chikuma, Takashi Akanuma, and Hiroko Nakatsukasa Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Correspondence: [email protected] Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene tran- scriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4þ T cells and the maturation of CD8þ T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity. here are four types of the cytokine receptors: (ERK) pathway (see Fig. 1). Any receptor that T(1) receptors that activate nuclear factor activates intracellular signaling pathways has (NF)-kB and mitogen-activated protein (MAP) multiple negative feedback systems, which en- kinases (mainly p38 and c-Jun amino-terminal sures transient activation of the pathway and kinase [JNK]), such as receptors for the tumor downstream transcription factors. Typical neg- necrosis factor (TNF)-a family, the interleukin ative regulators are shown in Figure 1. Lack of (IL)-1 family, including IL-1b, IL-18, and IL- such negative regulators results in autoimmune 33, and the IL-17 family; (2) receptors that diseases, autoinflammatory diseases, and some- activate the Janus kinase and signal transducers times-fatal disorders, including cancer. -
Crystal Structure of the SOCS2–Elongin C–Elongin B Complex Defines a Prototypical SOCS Box Ubiquitin Ligase
Crystal structure of the SOCS2–elongin C–elongin B complex defines a prototypical SOCS box ubiquitin ligase Alex N. Bullock*, Judit E.´ Debreczeni*, Aled M. Edwards†, Michael Sundstro¨ m*, and Stefan Knapp*‡ *Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, United Kingdom; and †Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5S 1A8 Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved March 27, 2006 (received for review February 28, 2006) Growth hormone (GH) signaling is tightly controlled by ubiquiti- patients with gigantism (8). The effect of SOCS2 is mediated by nation of GH receptors, phosphorylation levels, and accessibility of signaling through the JAK͞STAT pathway, as demonstrated by binding sites for downstream signaling partners. Members of the STAT5b͞SOCS2 double knockout mice, which have no over- suppressors of cytokine signaling (SOCS) family function as key growth phenotype (9). Furthermore, SOCS2 knockout neural regulators at all levels of this pathway, and mouse knockout stem cells are 100-fold more sensitive to GH and produce 50% studies implicate SOCS2 as the primary suppressor. To elucidate the fewer neurons than wild type, pointing to an important role for structural basis for SOCS2 function, we determined the 1.9-Å SOCS2 in cell differentiation (10). crystal structure of the ternary complex of SOCS2 with elongin C SOCS proteins contain three domains necessary for SOCS2 and elongin B. The structure defines a prototypical SOCS box regulation of GHR signaling: a variable N-terminal domain, a ubiquitin ligase with a Src homology 2 (SH2) domain as a substrate central SH2 domain, and a conserved SOCS box in the C- recognition motif. -
Mapping Human Hematopoietic Hierarchy at Single Cell Resolution by Microwell-Seq
bioRxiv preprint doi: https://doi.org/10.1101/127217; this version posted April 13, 2017. 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. Mapping Human Hematopoietic Hierarchy at Single Cell Resolution by Microwell-seq Shujing Lai1,8,9, Yang Xu1,8,9, Wentao Huang1,9, Mengmeng Jiang1,8, 9, Haide Chen1,8, Fang Ye1, Renying Wang1, Yunfei Qiu 2, Xinyi Jiang1, Daosheng Huang1,8, Jie Mao3, Yanwei Li 4, Yingru Lu5, Jin Xie6, Qun Fang7,Tiefeng Li3, He Huang2,8, Xiaoping Han1,8 & Guoji Guo1,8* 1Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China 2The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 3Institute of Applied Mechanics, Zhejiang University, Hangzhou 310027, China 4Core Facilities, Zhejiang University School of Medicine, Hangzhou 310058, China 5Department of Emergency Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China 6Institute of Mechatronic Control Engineering, Zhejiang University, Hangzhou 310027, China 7Institute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou, 310058, China 8Stem Cell Institute, Zhejiang University, Hangzhou 310058, China 9These authors contributed equally to this work * Correspondence: (G.G.) [email protected]; Summary: The classical hematopoietic hierarchy, which is mainly built with fluorescence-activated cell sorting (FACS) technology, proves to be inaccurate in recent studies. Single cell RNA-seq (scRNA-seq) analysis provides a solution to overcome the limit of FACS-based cell type definition system for the dissection of complex cellular hierarchy. -
189 1. ABSTRACT 2. INTRODUCTION SOCS2: Physiological And
[Frontiers in Bioscience, Elite, 8, 189-204, January 1, 2016] SOCS2: physiological and pathological functions Elisabeth Letellier1, Serge Haan1 1Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, 162A avenue de la Faïencerie, L-1511 Luxembourg, Luxembourg TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Biological functions of SOCS2 4. SOCS2 function in the immune system 5. SOCS2 function in the CNS 6. SOCS2 in cancer 7. Structure-function aspects for SOCS2 SNPs reported in tumour tissues 8. Acknowledgements 9. References 1. ABSTRACT Suppressors of cytokine signalling (SOCS) disorders in haematopoiesis and autoimmune diseases. proteins are modulators of cytokine and growth factor A number of key regulatory proteins, such as the protein signalling whose aberrant regulation has been linked inhibitors of activated STATs (PIAS), the Src-homology to a variety of inflammatory and neoplastic diseases. 2 (SH2) -containing protein tyrosine phosphatases SOCS proteins are able to act as substrate-recruiting (SHPs) and the protein family of suppressors of cytokine component of E3-ubiquitin ligase complexes and target signalling (SOCS) control cytokine responses. interacting proteins for degradation. At least some of the family members can also directly inhibit tyrosine SOCS proteins, which emerged since their kinases such as Janus Kinases (JAK). The most studied discovery in 1999 as the main regulator of cytokine family members, CIS, SOCS1, SOCS2 and SOCS3 are signalling, are rapidly induced upon JAK/STAT important regulators of the JAK-STAT pathway. Here, we signalling by activated signal transducer and activator focus on SOCS2 and review its biological function as well of transcription factors (STATs) to negatively regulate as its implication in pathological processes. -
The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication Sonzogni, O Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-71661 Dissertation Published Version Originally published at: Sonzogni, O. The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replica- tion. 2012, University of Zurich, Faculty of Science. The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Olmo Sonzogni von Moleno, TI Promotionskomitee: Prof. Dr. Nicolas J. Müller (Leitung der Dissertation) Prof. Dr. Christoph Renner (Vorsitz) Prof. Dr. Amedeo Caflisch Zürich, 2012 To my parents Dissertation Table of contents 1. Summary......................................................................................................................9 2. Zusammenfassung ...................................................................................................11 3. Introduction ...............................................................................................................13 3.1 Human cytomegalovirus .........................................................................................13 3.1.1 Epidemiology and