DOCSLIB.ORG

Mechanisms of Granule-Dependent Killing

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanisms of Granule-Dependent Killing Cell Death and Differentiation (2008) 15, 251–262 & 2008 Nature Publishing Group All rights reserved 1350-9047/08 $30.00 www.nature.com/cdd Review Mechanisms of granule-dependent killing SP Cullen1 and SJ Martin*,1 Cytotoxic T lymphocyte and natural killer cell-initiated cell death is one of the primary mechanisms used by higher organisms to eliminate viruses and transformed cells. In this context, target cell death is rapid and efficient and initiated via two main pathways, involving either the ligation of death receptors or through the granule-exocytosis pathway. The granule-exocytosis pathway has attracted much attention over the past 10 years and consequently, a mechanism for granule-dependent killing has become reasonably well established. In the granule-dependent pathway, several proteolytic enzymes called granzymes are delivered to the target cell, promoting the activation of a family of death-inducing proteases called caspases. If caspases are inhibited by viral proteins or are inactivated through mutation, granzyme-mediated proteolysis of other cellular substrates ensures the timely death of infected or transformed cells. Here, we examine the findings that have shaped our current understanding of the mechanics of granule-dependent killing and discuss recent insights that have clarified some long-standing discrepancies in the granzyme literature. Cell Death and Differentiation (2008) 15, 251–262; doi:10.1038/sj.cdd.4402244; published online 2 November 2007 Apoptosis is an innate mechanism of programmed cell death the antigen-presenting cell, of class I major histocompatibility that enables multicellular organisms to eliminate unwanted complex (MHC) proteins, which bind intracellular antigenic cells and constitutes the most common form of cell death in peptides and carry them to the cell surface where they are the body that occurs during development, tissue remodelling, presented along with a co-stimulatory signal, to the CTL. Once cell homeostasis and during the response of the immune activated, CTLs can recognize the same class I MHC-peptide system to viral infection and cellular transformation.1 Internal complex on the surface of a virus-infected cell. Upon surveillance systems constantly monitor the intracellular encounter of specific antigen for the first time, T cells are environment, determining when a cell has reached the end induced to clonally expand in order to combat the infection and of its useful life or has become defective in some way. In this can take several days. The ‘memory’ of this first antigen response to a variety of cues, a conserved program of cell encounter is facilitated by the production of memory T cells, death is initiated, culminating in the orderly dismantling of the which ensures a much faster and more aggressive response cell.2,3 Proximal in this process and key players in the when the antigen is encountered for the second time. Natural molecular control of apoptosis are proteins of the BCL-2 killer (NK) cells play a pivotal role in the innate immune family, which orchestrate the downstream activation of system.8 Unlike T cells, they do not require pre-activation by caspases.4,5 Activated caspases then cleave a diverse cohort dendritic cells and are thus important in the early stages of of protein substrates resulting in the rapid and efficient death infection, before the T-cell response is fully underway. of the cell.3 However, this surveillance mechanism can be Although this is the case in humans, a recent study has corrupted by mutation, in some cases leading to cellular highlighted differences in perforin and granzyme expression transformation. In addition, many viruses employ strategies to between human and murine NK cells.9 Human NK cells sabotage the cell death programme of infected cells,6,7 as this constitutively express perforin and granzymes A and B.9 appears to be the main defensive strategy utilized by the host However, whereas resting murine NK cells contain plentiful to destroy the invader. In such situations, the cell-mediated granzyme A but little perforin or granzyme B, upon activation, immune response is necessary for the removal of tumorigenic the levels of perforin and granzyme B within murine NK cells and virus infected cells. substantially increase with a commensurate increase in Cytotoxic T lymphocytes (CTL) are initially activated in the cytotoxicity.9 The differences in the regulation of perforin peripheral lymphoid organs by recognizing foreign antigen and granzyme expression between mouse and man suggests presented on the surface of an antigen-presenting cell, usually that there may be substantial differences between the a dendritic cell. This recognition depends on the presence, in immune systems of different species and that care must be 1Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland *Corresponding author: SJ Martin, Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, D2, Ireland. Tel: þ 353 1 896 1289; Fax: þ 353 1 679 8558; E-mail: [email protected] Keywords: apoptosis; CTL; NK cell; granzyme; perforin Abbreviations: CAD, caspase-activated DNase; cSMAC, central supramolecular activation complex; CTL, cytotoxic T lymphocyte; DNA-PK, DNA-dependent protein kinase; FHL, familial hemophagocytic lymphohistiocytosis; ICAD, inhibitor of caspase-activated DNase; MCMV, murine cytomegalovirus; MHC, major histocompatibility complex; MTOC, microtubule organizing centre; NK, natural killer; NUMA, nuclear mitotic apparatus protein; PI-9, protease inhibitor-9; ROS, reactive oxygen species; Treg, T regulatory Received 03.5.07; revised 07.9.07; accepted 11.9.07; Edited by G Melino; published online 02.11.07 Mechanisms of granule-dependent killing SP Cullen and SJ Martin 252 taken when extrapolating mouse data to humans, a point swiftly along microtubules in the direction of the plasma which will be returned to later in the review. NK cells can membrane.19 recognize and kill virally infected or tumor cells and can rapidly Both albinism and immune deficiencies are symptomatic of produce cytokines and chemokines, which have immune a number of genetic disorders associated with the dysfunction stimulatory and antimicrobial effects.10 NK cell activation has of CTLs and melanocytes, both of which contain secretory been studied extensively in recent years and is discussed lysosomes. Secretory lysosome function is impaired in these elsewhere in this issue.11 individuals and the study of such disorders has greatly CTLs can kill their targets through one of two main advanced our understanding of the mechanisms of cytotoxic pathways. CTLs expressing ligands of the tumor necrosis granule secretion. Individuals with Hermansky–Pudlak syn- factor superfamily on their cell surface can kill target cells drome type 2 lack the cytosolic adapter protein 3 (AP-3), expressing the corresponding receptors, whereas NK cells which has been shown to be important for granule movement appear to rely predominantly on the granule-dependent along microtubules and because of this, CTLs from these pathway. The second cell death pathway involving the individuals show a substantial loss of cytotoxic activity.20 perforin-mediated trafficking of a family of proteases, called When the granules move toward the interface between granzymes, from CTL/NK cells to the target cell cytosol effector and target, Rab27a, missing in Griscelli syndrome, (Figure 1), is the focus of this review. is thought to be required for movement of the granules from the MTOC to the plasma membrane.21–23 The 400 kDa protein, Lyst, lacking in Chediak–Higashi syndrome, has Granule-Dependent Killing been implicated in the fusion of granules with the plasma A major mechanism of CTL/NK cell-mediated killing involves membrane.24,25 A more recent study has highlighted the the delivery of secretary lysosomes, or granules, into the importance of Munc13-4, mutated in familial hemophagocytic immunological synapse between the effector and its tar- lymphohistiocytosis subtype 3 (FHL3), in the priming of get.12,13 In CTLs, the granules are synthesized only after the granules, which precedes membrane fusion.26,27 cell has encountered specific antigen and has become After the cytotoxic granules have been polarized at the activated,12 whereas in NK cells, cytotoxic granules cell membrane, they are secreted into the immunological are formed during development. Therefore, NK cells are synapse in an ordered sequence of events. Target-effector equipped to respond rapidly to the threat of tumorigenicity cell contact triggers the accumulation of talin and adhesion or infection.14 The major granule components are perforin molecules at the contact site, which combine to form a and granzymes, which, upon delivery to the target, combine circular structure that binds and stabilizes the polarized to engineer rapid cell death with killing time as short as MTOC.28,29 This structure surrounds a central supra- 20 min.15 Recognition of a target by a CTL cell triggers rapid molecular activation complex (cSMAC) through which the polarization of the microtubule organizing center (MTOC) polarized granules pass before secretion.28 The final step i toward the immunological synapse,16–18 with granules moving n the process of granule delivery is accomplished when the Figure 1 Time course of NK-mediated killing. The NK cell line, YT, was used to kill HeLa cell targets and images were recorded at 1-min intervals. The frames shown represent 20-min intervals between
Load more

Recommended publications
  • Granzyme a Released Upon Stimulation of Cytotoxic T Lymphocytes Activates the Thrombin Receptor on Neuronal Cells and Astrocytes HANA S
    Proc. Nail. Acad. Sci. USA Vol. 91, pp. 8112-8116, August 1994 Neurobiology Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes HANA S. SUIDAN*, JACQUES BOUVIERt, ESTHER SCHAERERt, STUART R. STONES, DENIS MONARD*, AND JURG TSCHOPPt *Fnednch Miescher-Institut, P.O. Box 2543, CH-4002 Basel, Switzerland; tInstitute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; and tDepartment of Haematology, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom Communicated by Hans Neurath, May 4, 1994 ABSTRACT Granzymes are a family of serine proteases for example, myelin destruction is believed to be mediated by that are harbored in cytoplasmic granules of activated T these immune effector cells (19, 20). Experimental autoim- lymphocytes and are released upon target cell interaction. mune encephalomyelitis (EAE), a rodent multiple sclerosis- Immediate and complete neurite retraction was induced in a like disease, can be caused by T lymphocytes reactive against mouse neuronal cell line when total extracts ofgranule proteins myelin basic protein (MBP) (21). The encephalitogenic MBP- were added. This activity was isolated and identified as gran- specific T lymphocytes are in most cases CD4+ and major zyme A. This protease not only induced neurite retraction at histocompatibility complex class lI-restricted (17). The nanomolar concentrations but also reversed the stellation of pathogenicity in the central nervous system involves homing, astrocytes. Both effects were critically dependent on the ester- extravasation, and induction of tissue damage. olytic activity of granzyme A. As neurite retraction is known to Little is known about the molecular mechanism by which be induced by thrombin, possible cleavage and activation ofthe encephalitogenic T lymphocytes induce tissue destruction in thrombin receptor were investigated.
    [Show full text]
  • Defining the Characteristics of Serine Protease-Mediated Cell Death Cascades ⁎ A.R
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1773 (2007) 1491–1499 www.elsevier.com/locate/bbamcr Minireview A more serine way to die: Defining the characteristics of serine protease-mediated cell death cascades ⁎ A.R. O’Connell, C. Stenson-Cox National Centre for Biomedical and Engineering Science, National University of Ireland, Galway, Ireland Received 23 February 2007; received in revised form 11 July 2007; accepted 1 August 2007 Available online 14 August 2007 Abstract The morphological features observed by Kerr, Wylie and Currie in 1972 define apoptosis, necrosis and autophagy. An appreciable number of alternative systems do not fall neatly under these categories, warranting a review of alternative proteolytic machinery and its contribution to cell death. This review aims to pinpoint key molecular features of serine protease-mediated pro-apoptotic signalling. The profile created will contribute to a standard set of biochemical criteria that can serve in differentiating within cell death subtypes. © 2007 Elsevier B.V. All rights reserved. Keywords: Apoptosis; Serine protease; Caspase; Mitochondria 1. Introduction ability (MOMP) triggering the release of apoptogenic factors. Although the underlying mechanism of MOMP induction has The knowledge that cell death is an essential event in the life not been fully ascertained it is known to be regulated by of multi-cellular organisms has been around for more than members of the Bcl-2 family (Fig. 11). Anti-apoptotic Bcl-2 and 150 years. In 1972 Kerr et al., coined the term ‘apoptosis’ to Bcl-xl proteins block MOMP, whilst pro-apoptotic BH-3 describe a distinct morphological pattern of physiologically domain only proteins; Bim and Bid promote MOMP through occurring cell death [1].
    [Show full text]
  • Cells and at Immune-Privileged Sites Dendritic Inhibitor 9, Is Mainly
    The Granzyme B Inhibitor, Protease Inhibitor 9, Is Mainly Expressed by Dendritic Cells and at Immune-Privileged Sites1 Bellinda A. Bladergroen,* Merel C. M. Strik,† Niels Bovenschen,* Oskar van Berkum,* George L. Scheffer,* Chris J. L. M. Meijer,* C. Erik Hack,†‡ and J. Alain Kummer2* Granzyme B is released from CTLs and NK cells and an important mediator of CTL/NK-induced apoptosis in target cells. The human intracellular serpin proteinase inhibitor (PI)9 is the only human protein able to inhibit the activity of granzyme B. As a first step to elucidate the physiological role of PI9, PI9 protein expression in various human tissues was studied. A mAb directed against human PI9 was developed, which specifically stained PI9-transfected COS-7 cells, and was used for immunohistochem- istry. Both in primary lymphoid organs and in inflammatory infiltrates, PI9 was present in different subsets of dendritic cells. Also T-lymphocytes in primary and organ-associated lymphoid tissues were PI9 positive. Endothelial cells of small vessels in most organs tested as well as the endothelial layer of large veins and arteries showed strong PI9 staining. Surprisingly, high PI9 protein expression was also found at immune-privileged sites like the placenta, the testis, the ovary, and the eye. These data fit with the hypothesis that PI9 is expressed at sites where degranulation of CTL or NK cells is potentially deleterious. The Journal of Immunology, 2001, 166: 0000–0000. ytotoxic cells such as NK cells and CTL form an impor- phocytes, and Fas-associated death domain-like IL-1-converting tant line of defense against virally infected cells and tu- enzyme-inhibitory protein (3), which directly inhibits the Fas-me- C mor cells.
    [Show full text]
  • Granzyme a in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging
    Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging This information is current as Robert A. Campbell, Zechariah Franks, Anish Bhatnagar, of November 27, 2017. Jesse W. Rowley, Bhanu K. Manne, Mark A. Supiano, Hansjorg Schwertz, Andrew S. Weyrich and Matthew T. Rondina J Immunol published online 22 November 2017 http://www.jimmunol.org/content/early/2017/11/22/jimmun Downloaded from ol.1700885 Supplementary http://www.jimmunol.org/content/suppl/2017/11/22/jimmunol.170088 Material 5.DCSupplemental http://www.jimmunol.org/ Why The JI? • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on November 27, 2017 • Speedy Publication! 4 weeks from acceptance to publication *average 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 22, 2017, doi:10.4049/jimmunol.1700885 The Journal of Immunology Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging Robert A. Campbell,*,† Zechariah Franks,* Anish Bhatnagar,* Jesse W. Rowley,*,‡ Bhanu K. Manne,* Mark A.
    [Show full text]
  • Yang2012.Pdf
    This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Characterization of bovine granzymes and studies of the role of granzyme B in killing of Theileria -infected cells by CD8+ T cells Jie Yang PhD by Research The University of Edinburgh 2012 Declaration I declare that the work presented in this thesis is my own original work, except where specified, and it does not include work forming part of a thesis presented successfully for a degree in this or another university Jie Yang Edinburgh, 2012 i Abstract Previous studies have shown that cytotoxic CD8+ T cells are important mediators of immunity against the bovine intracellular protozoan parasite T. parva . The present study set out to determine the role of granule enzymes in mediating killing of parasitized cells, first by characterising the granzymes expressed by bovine lymphocytes and, second, by investigating their involvement in killing of target cells.
    [Show full text]
  • Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer
    Author Manuscript Published OnlineFirst on July 29, 2019; DOI: 10.1158/0008-5472.CAN-19-0086 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Inactivation of proprotein convertases in T cells inhibits PD-1 expression and creates a favorable immune microenvironment in colorectal cancer Mercedes Tomé,1,2 Angela Pappalardo,3 Fabienne Soulet,1,2 José Javier López,4 Jone Olaizola,1,2 Yannick Leger,1,2 Marielle Dubreuil,1,2 Amandine Mouchard,1,5 Delphine Fessart, 5,6 Frédéric Delom, 5,6 Vincent Pitard,3 Dominique Bechade,5 Mariane Fonck,5 Juan Antonio Rosado,4 François Ghiringhelli,7 Julie Déchanet-Merville,3 Isabelle Soubeyran,5 Geraldine Siegfried,1,2 Serge Evrard,1,2,5,* Abdel-Majid Khatib,1,2,* *: Equal Contributions 1 Université Bordeaux, 33000, Bordeaux, France 2 INSERM UMR1029, 33400, Pessac, France 3 ImmunoConcept, CNRS UMR 5164, University of Bordeaux, F-33000 Bordeaux, France 4 Department of Physiology, Veterinary Faculty, University of Extremadura, 10003 Caceres, Spain. 5 Institut Bergonié, Bordeaux, France 6 INSERM U1218, ACTION, Bordeaux, France. 7 INSERM UMR1231, Dijon, France. Corresponding authors: [email protected]; Phone: 33-540002953 and [email protected]; Phone: 33-540008705 INSERM U1029, Bordeaux University, Bat. B2 Ouest Allée Geoffroy St Hilaire CS50023, 33615 PESSAC CEDEX Running Title: Proprotein Convertases and PD-1 expression Keywords: Proprotein convertases, furin, PD-1, cancer immunoresponse, T-cells, cytotoxicity 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 29, 2019; DOI: 10.1158/0008-5472.CAN-19-0086 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells with an Increased Cytotoxic Potential
    + CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells.
    [Show full text]
  • Granzyme a in Chikungunya and Other Arboviral Infections
    ORIGINAL RESEARCH published: 14 January 2020 doi: 10.3389/fimmu.2019.03083 Granzyme A in Chikungunya and Other Arboviral Infections Alessandra S. Schanoski 1*†, Thuy T. Le 2†, Dion Kaiserman 3, Caitlin Rowe 3, Natalie A. Prow 2,4, Diego D. Barboza 1, Cliomar A. Santos 5, Paolo M. A. Zanotto 6, Kelly G. Magalhães 7, Luigi Aurelio 8, David Muller 9, Paul Young 9, Peishen Zhao 8, Phillip I. Bird 3‡ and Andreas Suhrbier 2,4*‡ 1 Bacteriology Laboratory, Butantan Institute, São Paulo, Brazil, 2 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, 3 Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia, 4 Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia, 5 Health Foundation Parreiras Horta, Central Laboratory of Public Health, State Secretary for Health, Aracajú, Brazil, 6 Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil, 7 Laboratory of Immunology and Inflammation, University of Brasilia, Brasilia, Brazil, 8 Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Edited by: Parkville, VIC, Australia, 9 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, Australia Lisa F. P. Ng, Singapore Immunology Network (A∗STAR), Singapore Granzyme A (GzmA) is secreted by cytotoxic lymphocytes and has traditionally been Reviewed by: viewed as a mediator of cell death. However, a growing body of data suggests the Pierre Roques, physiological role of GzmA is promotion of inflammation. Here, we show that GzmA is CEA Saclay, France Julian Pardo, significantly elevated in the sera of chikungunya virus (CHIKV) patients and that GzmA Fundacion Agencia Aragonesa para la levels correlated with viral loads and disease scores in these patients.
    [Show full text]
  • Multi-SNP Analysis of GWAS Data Identifies Pathways Associated With
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2013 Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease Qing-Rong Chen National Cancer Institute, National Institutes of Health, Bethesda Rosemary Braun National Cancer Institute, National Institutes of Health, Bethesda Ying Hu National Cancer Institute, National Institutes of Health, Bethesda Chunhua Yan National Cancer Institute, National Institutes of Health, Bethesda Elizabeth M. Brunt Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Chen, Qing-Rong; Braun, Rosemary; Hu, Ying; Yan, Chunhua; Brunt, Elizabeth M.; Meerzaman, Daoud; Sanyal, Arun J.; and Buetow, Kenneth, ,"Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease." PLoS One.8,7. e65982. (2013). https://digitalcommons.wustl.edu/open_access_pubs/1598 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Qing-Rong Chen, Rosemary Braun, Ying Hu, Chunhua Yan, Elizabeth M. Brunt, Daoud Meerzaman, Arun J. Sanyal, and Kenneth Buetow This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/1598 Multi-SNP Analysis of GWAS Data Identifies Pathways Associated with Nonalcoholic Fatty Liver Disease Qing-Rong Chen1*, Rosemary Braun1,2, Ying Hu1, Chunhua Yan1, Elizabeth M. Brunt3, Daoud Meerzaman1, Arun J. Sanyal4., Kenneth Buetow1,5. 1 Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Biostatistics Division, Department of Preventive Medicine and Robert H.
    [Show full text]
  • Proteolytic Cleavage—Mechanisms, Function
    Review Cite This: Chem. Rev. 2018, 118, 1137−1168 pubs.acs.org/CR Proteolytic CleavageMechanisms, Function, and “Omic” Approaches for a Near-Ubiquitous Posttranslational Modification Theo Klein,†,⊥ Ulrich Eckhard,†,§ Antoine Dufour,†,¶ Nestor Solis,† and Christopher M. Overall*,†,‡ † ‡ Life Sciences Institute, Department of Oral Biological and Medical Sciences, and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada ABSTRACT: Proteases enzymatically hydrolyze peptide bonds in substrate proteins, resulting in a widespread, irreversible posttranslational modification of the protein’s structure and biological function. Often regarded as a mere degradative mechanism in destruction of proteins or turnover in maintaining physiological homeostasis, recent research in the field of degradomics has led to the recognition of two main yet unexpected concepts. First, that targeted, limited proteolytic cleavage events by a wide repertoire of proteases are pivotal regulators of most, if not all, physiological and pathological processes. Second, an unexpected in vivo abundance of stable cleaved proteins revealed pervasive, functionally relevant protein processing in normal and diseased tissuefrom 40 to 70% of proteins also occur in vivo as distinct stable proteoforms with undocumented N- or C- termini, meaning these proteoforms are stable functional cleavage products, most with unknown functional implications. In this Review, we discuss the structural biology aspects and mechanisms
    [Show full text]
  • Granzyme a Is Critical for Recovery of Mice from Infection With
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 5783-5787, June 1996 Immunology Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia (poxvirus/cytolytic leukocytes/proteases) ARNO MULLBACHER*, KLAUS EBNETtS, ROBERT V. BLANDEN*, RON THA HLA*, THOMAS STEHLEt, CRISAN MUSETEANUt, AND MARKUS M. SIMONt§ *Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, Canberra City, Australian Capital Territory 2601, Australia; and tMax-Planck-Institut for Immunbiology, Stiibeweg 51, D-79108 Freiburg, Germany Communicated by Frank Fenner, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia, February 7, 1996 (received for review December 6, 1995) ABSTRACT Cytolytic lymphocytes are of cardinal impor- normal littermates between 6 and 12 weeks of age were used tance in the recovery from primary viral infections. Both throughout the experiments. natural killer cells and cytolytic T cells mediate at least part Viruses. The virulent Moscow strain ectromelia virus was of their effector function by target cell lysis and DNA frag- grown in mouse spleen, the intracellular naked ectromelia mentation. Two proteins, perforin and granzyme B, contained virus (INV), and the extracellular enveloped ectromelia virus within the cytoplasmic granules ofthese cytolytic effector cells (EEV) in tissue culture, as has been described previously (12, have been shown to be directly involved in these processes. A 13). Viruses were purified and titrated on BS-C-1 monkey cell third protein contained within these granules, granzyme A, monolayers as has been described (14). The predominance of has so far not been attributed with any biological relevance.
    [Show full text]
  • Mycobacterium Tuberculosis Activation Following Stimulation by T Cell +
    Differential Gene Expression Identifies Novel Markers of CD4 + and CD8+ T Cell Activation Following Stimulation by Mycobacterium tuberculosis This information is current as of September 23, 2021. Jacqueline M. Cliff, Iryna N. J. Andrade, Rohit Mistry, Christopher L. Clayton, Mark G. Lennon, Alan P. Lewis, Ken Duncan, Pauline T. Lukey and Hazel M. Dockrell J Immunol 2004; 173:485-493; ; doi: 10.4049/jimmunol.173.1.485 Downloaded from http://www.jimmunol.org/content/173/1/485 Supplementary http://www.jimmunol.org/content/suppl/2004/06/17/173.1.485.DC1 http://www.jimmunol.org/ Material References This article cites 51 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/173/1/485.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Gene Expression Identifies Novel Markers of CD4؉ and CD8؉ T Cell Activation Following Stimulation by Mycobacterium tuberculosis1 Jacqueline M.
    [Show full text]