The Human Apoptosis-Inducing Granzyme M Structural Basis For
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Transplant Immunology
Basic Immunology in Medical Practice น.พ. สกานต์ บุนนาค งานโรคไต กลุ่มงานอายุรศาสตร์ รพ.ราชวิถี Basic immunology • Innate immunity • Ready to be used • Less specificity • Comprise of • External barriers: skin, mucus, washing fluid etc. • Molecule: complement, acute-phase protein and cytokine • inflammatory mediator secreting cells: basophil, mast cell, eosinophil and natural killer cell • Phagocytic cells: neutrophil, monocyte, and macrophage Basis immunology • Adaptive immunity • Active after expose to specific Ag. • High specificity • Comprise of • Humoral immune response (HIR) : B lymphocyte, Memory B lymphocyte, plasma cell and antibody • Cell mediated immune response (CMIR) : T lymphocyte • Effector T lymphocyte • CD4+ T cell Helper T cell (Th1, Th2, Th17 etc.) • CD8+ T cell Cytotoxic T cell • Regulatory T lymphocyte • Memory T lymphocyte Innate immunity Cellular component of innate immunity • Activated by pathogen-associated molecular patterns (PAMPs) via pattern reconition receptors (PRRs). • PAMPs • Shared by a larged group of infectious agens • Unlikely to mutate • Clearly distinguishable from self pattern (commonly not present on mammalian cell surface • Gram-negative LPS, gram-positive lipoteichoic acid, yeast cell wall mannan etc. Phagocytic cells • Neutrophils, monocyte and macrophage • Killing machanisms • Reactive oxygen radicals • Oxygen-independent machanism: α – defencin, cathepsin G, lysozyme, lactoferin etc. Mast cells Mast cells Natural killer (NK) cells Activating NK-R FAS-L perforin FAS Granzyme-B Caspase cascade -
Purification and Identification of a Binding Protein for Pancreatic
Biochem. J. (2003) 372, 227–233 (Printed in Great Britain) 227 Purification and identification of a binding protein for pancreatic secretory trypsin inhibitor: a novel role of the inhibitor as an anti-granzyme A Satoshi TSUZUKI*1,2,Yoshimasa KOKADO*1, Shigeki SATOMI*, Yoshie YAMASAKI*, Hirofumi HIRAYASU*, Toshihiko IWANAGA† and Tohru FUSHIKI* *Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan, and †Laboratory of Anatomy, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18-Nishi 9, Kita-ku, Sapporo 060-0818, Japan Pancreatic secretory trypsin inhibitor (PSTI) is a potent trypsin of GzmA-expressing intraepithelial lymphocytes in the rat small inhibitor that is mainly found in pancreatic juice. PSTI has been intestine. We concluded that the PSTI-binding protein isolated shown to bind specifically to a protein, distinct from trypsin, on from the dispersed cells is GzmA that is produced in the the surface of dispersed cells obtained from tissues such as small lymphocytes of the tissue. The rGzmA hydrolysed the N-α- intestine. In the present study, we affinity-purified the binding benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT), and the BLT protein from the 2 % (w/v) Triton X-100-soluble fraction of hydrolysis was inhibited by PSTI. Sulphated glycosaminoglycans, dispersed rat small-intestinal cells using recombinant rat PSTI. such as fucoidan or heparin, showed almost no effect on the Partial N-terminal sequencing of the purified protein gave a inhibition of rGzmA by PSTI, whereas they decreased the inhi- sequence that was identical with the sequence of mouse granzyme bition by antithrombin III. -
Original Article
Original Article Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9 George R. Lankas,1 Barbara Leiting,2 Ranabir Sinha Roy,2 George J. Eiermann,3 Maria G. Beconi,4 Tesfaye Biftu,5 Chi-Chung Chan,6 Scott Edmondson,5 William P. Feeney,7 Huaibing He,5 Dawn E. Ippolito,3 Dooseop Kim,5 Kathryn A. Lyons,5 Hyun O. Ok,5 Reshma A. Patel,2 Aleksandr N. Petrov,3 Kelly Ann Pryor,2 Xiaoxia Qian,5 Leah Reigle,5 Andrea Woods,8 Joseph K. Wu,2 Dennis Zaller,8 Xiaoping Zhang,2 Lan Zhu,2 Ann E. Weber,5 and Nancy A. Thornberry2 Dipeptidyl peptidase (DPP)-IV inhibitors are a new ap- important to an optimal safety profile for this new class of proach to the treatment of type 2 diabetes. DPP-IV is a antihyperglycemic agents. Diabetes 54:2988–2994, 2005 member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To deter- herapies that increase the circulating concentra- mine the importance of selective DPP-IV inhibition for the tions of insulin have proven beneficial in the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies treatment of type 2 diabetes. Dipeptidyl pepti- and in acute dog tolerability studies. In rats, the DPP8/9 Tdase (DPP)-IV inhibitors are a promising new inhibitor produced alopecia, thrombocytopenia, reticulocy- approach to type 2 diabetes that function, at least in part, topenia, enlarged spleen, multiorgan histopathological as indirect stimulators of insulin secretion (1). -
SARS-Cov-2 Entry Protein TMPRSS2 and Its Homologue, TMPRSS4
bioRxiv preprint doi: https://doi.org/10.1101/2021.04.26.441280; this version posted April 26, 2021. 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. 1 SARS-CoV-2 Entry Protein TMPRSS2 and Its 2 Homologue, TMPRSS4 Adopts Structural Fold Similar 3 to Blood Coagulation and Complement Pathway 4 Related Proteins ∗,a ∗∗,b b 5 Vijaykumar Yogesh Muley , Amit Singh , Karl Gruber , Alfredo ∗,a 6 Varela-Echavarría a 7 Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México b 8 Institute of Molecular Biosciences, University of Graz, Graz, Austria 9 Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes TMPRSS2 receptor to enter target human cells and subsequently causes coron- avirus disease 19 (COVID-19). TMPRSS2 belongs to the type II serine proteases of subfamily TMPRSS, which is characterized by the presence of the serine- protease domain. TMPRSS4 is another TMPRSS member, which has a domain architecture similar to TMPRSS2. TMPRSS2 and TMPRSS4 have been shown to be involved in SARS-CoV-2 infection. However, their normal physiological roles have not been explored in detail. In this study, we analyzed the amino acid sequences and predicted 3D structures of TMPRSS2 and TMPRSS4 to under- stand their functional aspects at the protein domain level. Our results suggest that these proteins are likely to have common functions based on their conserved domain organization. -
Serine Proteases with Altered Sensitivity to Activity-Modulating
(19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants. -
Death by Granzyme B
RESEARCH HIGHLIGHTS APOPTOSIS Death by granzyme B DOI: 10.1038/nri1951 The death of effector T cells following pro-apoptotic ligands and effector lysosomal-associated membrane pro- Link activation is an important process molecules in AICD of T 1 cells and tein 1 (LAMP1; a marker of granules) Granzyme B H http://www.ncbi.nlm.nih.gov/ in the termination of an immune TH2 cells. Blocking the pro-apoptotic was observed in both resting TH1 entrez/viewer.fcgi?db=protein response. However, the mechanisms molecule CD95 ligand (also known cells and resting TH2 cells. However, &val=1247451 that are involved in this activation- as FAS ligand) with specific agents following TCR engagement, colocali- induced cell death (AICD) through inhibited AICD of TH1 cells, as previ- zation was observed only in TH1 cells, engagement of the T-cell receptor ously reported. However, these agents indicating that granzyme B is released (TCR) are not well understood. Now, had no effect on the death of TH2 from the granules on activation of TH2 new research published in Immunity cells. Similarly, blocking the activity of cells but not TH1 cells. Interestingly, shows that granzyme B has an impor- several caspases affected only TH1-cell the amount of SPI6, which is a tant role in AICD of T helper 2 (TH2) death, whereas inhibition of TRAIL protease inhibitor that specifically cells. (tumour-necrosis-factor-related inhibits the activity of granzyme B, Examination of the kinetics of apoptosis-inducing ligand) did not was found to be increased in activated AICD, by staining for annexin V affect either cell type. -
A Novel CD4+ CTL Subtype Characterized by Chemotaxis and Inflammation Is Involved in the Pathogenesis of Graves’ Orbitopa
Cellular & Molecular Immunology www.nature.com/cmi ARTICLE OPEN A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves’ orbitopathy Yue Wang1,2,3,4, Ziyi Chen 1, Tingjie Wang1,2, Hui Guo1, Yufeng Liu2,3,5, Ningxin Dang3, Shiqian Hu1, Liping Wu1, Chengsheng Zhang4,6,KaiYe2,3,7 and Bingyin Shi1 Graves’ orbitopathy (GO), the most severe manifestation of Graves’ hyperthyroidism (GH), is an autoimmune-mediated inflammatory disorder, and treatments often exhibit a low efficacy. CD4+ T cells have been reported to play vital roles in GO progression. To explore the pathogenic CD4+ T cell types that drive GO progression, we applied single-cell RNA sequencing (scRNA-Seq), T cell receptor sequencing (TCR-Seq), flow cytometry, immunofluorescence and mixed lymphocyte reaction (MLR) assays to evaluate CD4+ T cells from GO and GH patients. scRNA-Seq revealed the novel GO-specific cell type CD4+ cytotoxic T lymphocytes (CTLs), which are characterized by chemotactic and inflammatory features. The clonal expansion of this CD4+ CTL population, as demonstrated by TCR-Seq, along with their strong cytotoxic response to autoantigens, localization in orbital sites, and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-γ-secreting CD4+ CTLs in GO. Therefore, cytotoxic pathways may become potential therapeutic targets for GO. 1234567890();,: Keywords: Graves’ orbitopathy; single-cell RNA sequencing; CD4+ cytotoxic T lymphocytes Cellular & Molecular Immunology -
A Triple-Mutated Allele of Granzyme B Incapable of Inducing Apoptosis
A triple-mutated allele of granzyme B incapable of inducing apoptosis Dorian McIlroy*†, Pierre-Franc¸ois Cartron‡, Pierre Tuffery§, Yasmine Dudoit*, Assia Samri*, Brigitte Autran*, Franc¸ois M. Vallette‡, Patrice Debre´ *, and Ioannis Theodorou*¶ *Laboratoire d’Immunologie Cellulaire et Tissulaire, Institut National de la Sante´et de la Recherche Me´dicale U543, Faculte´deMe´ decine Pitie´-Salpeˆtrie`re, 75013 Paris, France; ‡Institut National de la Sante´et de la Recherche Me´dicale U419, Institut de Biologie, 44000 Nantes, France; and §Institut National de la Sante´et de la Recherche Me´dicale U436, Equipe de Bioinformatique Ge´nomique et Mole´culaire, Universite´de Paris 7, 75013 Paris, France Communicated by Jean Dausset, Fondation Jean Dausset–Centre d’E´ tude du Polymorphisme Humain, Paris, France, December 27, 2002 (received for review June 6, 2002) Granzyme B (GzmB) is a serine protease involved in many pathol- resistant cell lines (20, 21). However, no congenital human ogies, including viral infections, autoimmunity, transplant rejec- diseases have been linked to the disruption of the GzmB gene, tion, and antitumor immunity. To measure the extent of genetic and GzmB knockout mice have no developmental or hemato- variation in GzmB, we screened the GzmB gene for polymorphisms logical abnormalities (22). Therefore, we hypothesized that, in and defined a frequently represented triple-mutated GzmB allele. contrast to mutations in the perforin gene (23), coding poly- 48 88 245 In this variant, three amino acids of the mature protein Q P Y morphisms in the GzmB gene might be relatively well tolerated ؉ 245 88 48 are mutated to R A H .InCD8 cytotoxic T lymphocytes, GzmB in humans and, if present, could influence the killing of tumor ͞ was expressed at similar levels in QPY homozygous, QPY RAH cells. -
Microarray Analysis of Novel Genes Involved in HSV- 2 Infection
Microarray analysis of novel genes involved in HSV- 2 infection Hao Zhang Nanjing University of Chinese Medicine Tao Liu ( [email protected] ) Nanjing University of Chinese Medicine https://orcid.org/0000-0002-7654-2995 Research Article Keywords: HSV-2 infection,Microarray analysis,Histospecic gene expression Posted Date: May 12th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-517057/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/19 Abstract Background: Herpes simplex virus type 2 infects the body and becomes an incurable and recurring disease. The pathogenesis of HSV-2 infection is not completely clear. Methods: We analyze the GSE18527 dataset in the GEO database in this paper to obtain distinctively displayed genes(DDGs)in the total sequential RNA of the biopsies of normal and lesioned skin groups, healed skin and lesioned skin groups of genital herpes patients, respectively.The related data of 3 cases of normal skin group, 4 cases of lesioned group and 6 cases of healed group were analyzed.The histospecic gene analysis , functional enrichment and protein interaction network analysis of the differential genes were also performed, and the critical components were selected. Results: 40 up-regulated genes and 43 down-regulated genes were isolated by differential performance assay. Histospecic gene analysis of DDGs suggested that the most abundant system for gene expression was the skin, immune system and the nervous system.Through the construction of core gene combinations, protein interaction network analysis and selection of histospecic distribution genes, 17 associated genes were selected CXCL10,MX1,ISG15,IFIT1,IFIT3,IFIT2,OASL,ISG20,RSAD2,GBP1,IFI44L,DDX58,USP18,CXCL11,GBP5,GBP4 and CXCL9.The above genes are mainly located in the skin, immune system, nervous system and reproductive system. -
Extended Cleavage Specificities of Two Mast Cell Chymase-Related
International Journal of Molecular Sciences Article Extended Cleavage Specificities of Two Mast Cell Chymase-Related Proteases and One Granzyme B-Like Protease from the Platypus, a Monotreme Zhirong Fu, Srinivas Akula , Michael Thorpe and Lars Hellman * Department of Cell and Molecular Biology, Uppsala University, Uppsala, The Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden; [email protected] (Z.F.); [email protected] (S.A.); [email protected] (M.T.) * Correspondence: [email protected]; Tel.: +46-(0)18-471-4532; Fax: +46-(0)18-471-4862 Received: 20 November 2019; Accepted: 31 December 2019; Published: 2 January 2020 Abstract: Mast cells (MCs) are inflammatory cells primarily found in tissues in close contact with the external environment, such as the skin and the intestinal mucosa. They store large amounts of active components in cytoplasmic granules, ready for rapid release. The major protein content of these granules is proteases, which can account for up to 35 % of the total cellular protein. Depending on their primary cleavage specificity, they can generally be subdivided into chymases and tryptases. Here we present the extended cleavage specificities of two such proteases from the platypus. Both of them show an extended chymotrypsin-like specificity almost identical to other mammalian MC chymases. This suggests that MC chymotryptic enzymes have been conserved, both in structure and extended cleavage specificity, for more than 200 million years, indicating major functions in MC-dependent physiological processes. We have also studied a third closely related protease, originating from the same chymase locus whose cleavage specificity is closely related to the apoptosis-inducing protease from cytotoxic T cells, granzyme B. -
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. -
The Human Genome Project
TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 TO KNOW OURSELVES ❖ THE U.S. DEPARTMENT OF ENERGY AND THE HUMAN GENOME PROJECT JULY 1996 Contents FOREWORD . 2 THE GENOME PROJECT—WHY THE DOE? . 4 A bold but logical step INTRODUCING THE HUMAN GENOME . 6 The recipe for life Some definitions . 6 A plan of action . 8 EXPLORING THE GENOMIC LANDSCAPE . 10 Mapping the terrain Two giant steps: Chromosomes 16 and 19 . 12 Getting down to details: Sequencing the genome . 16 Shotguns and transposons . 20 How good is good enough? . 26 Sidebar: Tools of the Trade . 17 Sidebar: The Mighty Mouse . 24 BEYOND BIOLOGY . 27 Instrumentation and informatics Smaller is better—And other developments . 27 Dealing with the data . 30 ETHICAL, LEGAL, AND SOCIAL IMPLICATIONS . 32 An essential dimension of genome research Foreword T THE END OF THE ROAD in Little has been rapid, and it is now generally agreed Cottonwood Canyon, near Salt that this international project will produce Lake City, Alta is a place of the complete sequence of the human genome near-mythic renown among by the year 2005. A skiers. In time it may well And what is more important, the value assume similar status among molecular of the project also appears beyond doubt. geneticists. In December 1984, a conference Genome research is revolutionizing biology there, co-sponsored by the U.S. Department and biotechnology, and providing a vital of Energy, pondered a single question: Does thrust to the increasingly broad scope of the modern DNA research offer a way of detect- biological sciences.