A TGF-Β– and P63-Responsive Enhancer Regulates IFN-Κ
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The C9orf72-Interacting Protein Smcr8 Is a Negative Regulator of Autoimmunity and Lysosomal Exocytosis
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis Yingying Zhang,1,2,3 Aaron Burberry,1,2,3 Jin-Yuan Wang,1,2,3 Jackson Sandoe,1,2,3 Sulagna Ghosh,1,2,3 Namrata D. Udeshi,4 Tanya Svinkina,4 Daniel A. Mordes,1,2,3,5 Joanie Mok,1,2,3 Maura Charlton,1,2,3 Quan-Zhen Li,6,7 Steven A. Carr,4 and Kevin Eggan1,2,3 1Department of Stem Cell and Regenerative Biology, 2Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA; 3Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA; 4Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 6Department of Immunology, 7Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA While a mutation in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generated Smcr8 loss-of-function mutant mice and found that they developed phenotypes also observed in C9orf72 loss-of- function animals, including autoimmunity. -
Retinoic Acid Enhances the Expression of Interferon-Induced Proteins: Evidence for Multiple Mechanisms of Action
Oncogene (1997) 15, 2349 ± 2359 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Retinoic acid enhances the expression of interferon-induced proteins: evidence for multiple mechanisms of action Luis Pelicano1, Fengsheng Li2, Christian Schindler2 and Mounira K Chelbi-Alix1 1CNRS-UPR 9051; 1, avenue Claude Vellefaux, HoÃpital St Louis, 75010 Paris, France; 2Division of Molecular Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA Retinoic acid (RA) and interferons (IFNs) are negative Tyk2, phosphorylate Stat1, Stat2 and Stat3. The IFN- regulators of cell proliferation. In vitro and in vivo, their stimulated gene factor 3 (ISGF3) is formed between combination leads to a more potent growth inhibition. Stat1 and Stat2 (Stat1 : 2) in association with the DNA- However, the molecular mechanisms by which RA and binding protein, p48, a member of the interferon IFNs potentiate each other are not fully understood. As regulatory factor (IRF) family (Fu et al., 1992; some IFN-induced gene products regulate cell growth Schindler et al., 1992). This complex binds to the and/or antiviral activity, we analysed the eects of RA IFN-stimulated response element (ISRE) found in on their expressions. RA increases the level of promoters of IFNa/b-stimulated genes. In addition, 2'5'oligoadenylate synthetase, p68 kinase, the promyelo- homo- and heterodimers of Stat1 and Stat3 (Stat1 : 1, cytic leukemia protein (PML) and Sp100 in both HL-60 Stat3 : 3 and Stat1 : 3) bind to a palindromic version of and WISH cells. Moreover, RA and IFN act coopera- the IFNg-activated site (GAS), regulating the expres- tively to increase the expression of these proteins. -
Antibody-Based Delivery of Cytokine Payloads to Carbonic Anhydrase IX
Published OnlineFirst June 18, 2019; DOI: 10.1158/1535-7163.MCT-18-1301 Large Molecule Therapeutics Molecular Cancer Therapeutics Antibody-Based Delivery of Cytokine Payloads to Carbonic Anhydrase IX Leads to Cancer Cures in Immunocompetent Tumor-Bearing Mice Barbara Ziffels1, Marco Stringhini1, Philipp Probst1, Tim Fugmann2, Theo Sturm2, and Dario Neri1 Abstract Antibody–cytokine fusion proteins can have the potential TNF, IL2, or IL12 as payloads cured all mice in their therapy to increase the density and activity of subsets of leukocytes groups, whereas only a subset of mice was cured by the within the tumor mass. Here, we describe the design, produc- antibody-based delivery of IFNa2. Although the antibody tion, and characterization of four novel antibody–cytokine fusion with TNF mediated a rapid hemorrhagic necrosis of fusion proteins directed against human carbonic anhydrase IX, the tumor mass, a slower regression of the neoplastic lesions a highly validated marker of hypoxia that is overexpressed in (which continued after the last injection) was observed with clear cell renal cell carcinoma and other malignancies. As the other fusion proteins, and treated mice acquired protective immunomodulatory payloads we used TNF, IL2, IFNa2 (cor- anticancer immunity. A high proportion of tumor-infiltrating þ responding to products that are in clinical use), and IL12 (as CD8 T cells was specific to the retroviral antigen AH1; this cytokine potently activates T cells and NK cells). Therapy however, the LGPGREYRAL peptide derived from human experiments were performed in BALB/c mice, bearing CT26 carbonic anhydrase IX was also present on tumor cells. The tumors transfected with human carbonic anhydrase IX, in results described herein provide a rationale for the clinical use order to assess the performance of the fusion proteins in an of fully human antibody–cytokine fusions specific to carbonic immunocompetent setting. -
Mechanism of Action Through an IFN Type I-Independent Responses To
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 is online at: average * The Journal of Immunology , 12 of which you can access for free at: 2012; 188:3088-3098; Prepublished online 20 from submission to initial decision 4 weeks from acceptance to publication February 2012; doi: 10.4049/jimmunol.1101764 http://www.jimmunol.org/content/188/7/3088 MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action Elena Caproni, Elaine Tritto, Mario Cortese, Alessandro Muzzi, Flaviana Mosca, Elisabetta Monaci, Barbara Baudner, Anja Seubert and Ennio De Gregorio J Immunol cites 33 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/2012/02/21/jimmunol.110176 4.DC1 This article http://www.jimmunol.org/content/188/7/3088.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 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 -
Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression
viruses Review Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression Hella Schwanke 1,2 , Markus Stempel 1,2 and Melanie M. Brinkmann 1,2,* 1 Institute of Genetics, Technische Universität Braunschweig, 38106 Braunschweig, Germany; [email protected] (H.S.); [email protected] (M.S.) 2 Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany * Correspondence: [email protected]; Tel.: +49-531-6181-3069 Received: 15 June 2020; Accepted: 3 July 2020; Published: 7 July 2020 Abstract: The type I interferon (IFN) response is a principal component of our immune system that allows to counter a viral attack immediately upon viral entry into host cells. Upon engagement of aberrantly localised nucleic acids, germline-encoded pattern recognition receptors convey their find via a signalling cascade to prompt kinase-mediated activation of a specific set of five transcription factors. Within the nucleus, the coordinated interaction of these dimeric transcription factors with coactivators and the basal RNA transcription machinery is required to access the gene encoding the type I IFN IFNβ (IFNB1). Virus-induced release of IFNβ then induces the antiviral state of the system and mediates further mechanisms for defence. Due to its key role during the induction of the initial IFN response, the activity of the transcription factor interferon regulatory factor 3 (IRF3) is tightly regulated by the host and fiercely targeted by viral proteins at all conceivable levels. In this review, we will revisit the steps enabling the trans-activating potential of IRF3 after its activation and the subsequent assembly of the multi-protein complex at the IFNβ enhancer that controls gene expression. -
4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4). -
Brain Sciences
brain sciences Article Differential Expression of Genes Related to Innate Immune Responses in Ex Vivo Spinal Cord and Cerebellar Slice Cultures Infected with West Nile Virus Parminder J. S. Vig 1,2,3,*, Deyin Lu 1, Amber M. Paul 4, Ram Kuwar 5, Maria Lopez 1, Dobrivoje S. Stokic 3,6 , A. Arturo Leis 6, Michael R. Garrett 7 and Fengwei Bai 1,4 1 Departments of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA; [email protected] (D.L.); [email protected] (M.L.); [email protected] (F.B.) 2 Biochemistry, University of Mississippi Medical Center, Jackson, MS 39216, USA 3 Neurobiology & Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS 39216, USA; [email protected] 4 Department of Biological Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA; [email protected] 5 Virginia Commonwealth University, Richmond, VA 23284, USA; [email protected] 6 Methodist Rehabilitation Center, Jackson, MS 39216, USA; [email protected] 7 Experimental Therapeutics and Pharmacology, University of Mississippi Medical Center, Jackson, MS 39216, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-601-984-5513; Fax: +1-601-984-6626 Received: 29 October 2018; Accepted: 18 December 2018; Published: 24 December 2018 Abstract: West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While neurons are a main target of WNV, other cell types, especially astrocytes, play an important role in promoting WNV-mediated central nervous system (CNS) damage. -
Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments
Author Manuscript Published OnlineFirst on November 29, 2017; DOI: 10.1158/0008-5472.CAN-17-1980 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments Anje Cauwels1†, Sandra Van Lint1†, Franciane Paul2, Geneviève Garcin2, Stefaan De Koker1,5, Alexander Van Parys1, Thomas Wueest3, Sarah Gerlo1, José Van der Heyden1, Yann Bordat2, Dominiek Catteeuw1, Elke Rogge1, Annick Verhee1, Bart Vandekerckhove4, Niko Kley3, Gilles Uzé2‡ & Jan Tavernier1,3‡* 1Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium. 2CNRS UMR 5235, University Montpellier, Place Eugène Bataillon, 34095 Montpellier, France. 3Orionis Biosciences, Technologiepark 4, 9052 Zwijnaarde-Gent, Belgium; and Watertown, Boston, USA. 4Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, UZ Gent, MRB2, De Pintelaan 185, 9000 Gent, Belgium 5Present address: eTheRNA Immunotherapies, Arthur de Coninckstraat 11, 3070 Kortenberg, Belgium *To whom correspondence should be addressed: Jan Tavernier, A. Baertsoenkaai 3, 9000 Ghent, Belgium. Phone +32.9.2649302, Fax +32.9.2649340, [email protected] †shared first authors, ‡shared last authors Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 29, 2017; DOI: 10.1158/0008-5472.CAN-17-1980 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 The authors declare no potential conflicts of interest. Running title: Specific DC-targeted IFN allows nontoxic antitumor efficacy This work was supported by UGent Methusalem and Advanced ERC (CYRE, N° 340941) grants to J.T.; an FWO-V grant G009614N to J.T. -
Type I Interferons in Anticancer Immunity
REVIEWS Type I interferons in anticancer immunity Laurence Zitvogel1–4*, Lorenzo Galluzzi1,5–8*, Oliver Kepp5–9, Mark J. Smyth10,11 and Guido Kroemer5–9,12 Abstract | Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic 1Gustave Roussy Cancer Campus, F-94800 Villejuif, viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the France. intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with 2INSERM, U1015, F-94800 Villejuif, France. favourable disease outcome in several cohorts of patients with cancer. Finally, new 3Université Paris Sud/Paris XI, anticancer immunotherapies are being developed that are based on recombinant type I IFNs, Faculté de Médecine, F-94270 Le Kremlin Bicêtre, France. type I IFN-encoding vectors and type I IFN-expressing cells. 4Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, F-94800 Villejuif, France. Type I interferons (IFNs) were first discovered more than Type I IFNs in cancer immunosurveillance 5Equipe 11 labellisée par la half a century ago as the factors underlying viral inter Type I IFNs are known to mediate antineoplastic effects Ligue Nationale contre le ference — that is, the ability of a primary viral infection against several malignancies, which is a clinically rel Cancer, Centre de Recherche 1 des Cordeliers, F-75006 Paris, to render cells resistant to a second distinct virus . -
Porcine Interferon Complex and Co-Evolution with Increasing Viral Pressure After Domestication
viruses Review Porcine Interferon Complex and Co-Evolution with Increasing Viral Pressure after Domestication Jordan Jennings and Yongming Sang * Department of Agricultural and Environmental Sciences, College of Agriculture, Tennessee State University, Nashville, TN 37209, USA; [email protected] * Correspondence: [email protected]; Tel.: +615-963-5183 Received: 17 May 2019; Accepted: 13 June 2019; Published: 15 June 2019 Abstract: Consisting of nearly 60 functional genes, porcine interferon (IFN)-complex represents an evolutionary surge of IFN evolution in domestic ungulate species. To compare with humans and mice, each of these species contains about 20 IFN functional genes, which are better characterized using the conventional IFN-α/β subtypes as examples. Porcine IFN-complex thus represents an optimal model for studying IFN evolution that resulted from increasing viral pressure during domestication and industrialization. We hypothesize and justify that porcine IFN-complex may extend its functionality in antiviral and immunomodulatory activity due to its superior molecular diversity. Furthermore, these unconventional IFNs could even confer some functional and signaling novelty beyond that of the well-studied IFN-α/β subtypes. Investigations into porcine IFN-complex will further our understanding of IFN biology and promote IFN-based therapeutic designs to confront swine viral diseases. Keywords: interferon; immune evolution; antiviral; porcine model 1. Introduction Interferons (IFNs) are a group of cytokines that have evolved in jawed vertebrates and bear a pivotal role in antiviral regulation as well as other biological functions [1–4]. Three types of IFNs, namely Type I, II, and III IFNs, have been defined based on their molecular signatures, interacting receptors, and signaling propensities in immune regulation [3,4]. -
CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity a C Suresh De Silva, George Fromm, Casey W
Published OnlineFirst December 18, 2019; DOI: 10.1158/2326-6066.CIR-19-0493 CANCER IMMUNOLOGY RESEARCH | RESEARCH ARTICLE CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity A C Suresh de Silva, George Fromm, Casey W. Shuptrine, Kellsey Johannes, Arpita Patel, Kyung Jin Yoo, Kaiwen Huang, and Taylor H. Schreiber ABSTRACT ◥ Disrupting the binding of CD47 to SIRPa has emerged as a No evidence of hemolysis, hemagglutination, or thrombocytopenia promising immunotherapeutic strategy for advanced cancers by was observed in vitro or in cynomolgus macaques. Murine SIRPa- potentiating antibody-dependent cellular phagocytosis (ADCP) of Fc-CD40L outperformed CD47 blocking and CD40 agonist anti- targeted antibodies. Preclinically, CD47/SIRPa blockade induces bodies in murine CT26 tumor models and synergized with immune antitumor activity by increasing the phagocytosis of tumor cells by checkpoint blockade of PD-1 and CTLA4. SIRPa-Fc-CD40L acti- macrophages and enhancing the cross-presentation of tumor anti- vated a type I interferon response in macrophages and potentiated þ gens to CD8 T cells by dendritic cells; both of these processes are the activity of ADCP-competent targeted antibodies both in vitro and potentiated by CD40 signaling. Here we generated a novel, two-sided in vivo. These data illustrated that whereas CD47/SIRPa inhibition fusion protein incorporating the extracellular domains of SIRPa and could potentiate tumor cell phagocytosis, CD40-mediated activation CD40L, adjoined by a central Fc domain, termed SIRPa-Fc-CD40L. of a type I interferon response provided a bridge between macro- SIRPa-Fc-CD40L bound CD47 and CD40 with high affinity and phage- and T-cell–mediated immunity that significantly enhanced activated CD40 signaling in the absence of Fc receptor cross-linking. -
IL6 Sensitizes Prostate Cancer to the Antiproliferative Effect of Ifna2
H H H Erb et al. IRF9 regulation by IL6 in 20:5 677–689 Research prostate cancer Open Access IL6 sensitizes prostate cancer to the antiproliferative effect of IFNa2 through IRF9 Holger H H Erb1, Regina V Langlechner1, Patrizia L Moser2, Florian Handle1, Tineke Casneuf3, Karin Verstraeten3, Bettina Schlick4, Georg Scha¨fer1, Brett Hall5, Kate Sasser5, Zoran Culig1 and Fre´de´ric R Santer1 Correspondence 1Division of Experimental Urology, Department of Urology 2Department of Pathology, Innsbruck Medical University, should be addressed 6020 Innsbruck, Austria to Z Culig or F R Santer 3Oncology Biomarkers, Janssen Research and Development, Beerse, Belgium Emails 4Oncotyrol, Center for Personalized Medicine, 6020 Innsbruck, Austria [email protected] or 5Oncology Biomarkers, Janssen Research and Development, Spring House, Pennsylvania, USA [email protected] Abstract Development and progression of prostate cancer (PCa) are associated with chronic Key Words inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, " IRF9 survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we " IL6 performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated " prostate cancer with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most " IFNa2 prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and " inflammation acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 Endocrine-Related Cancer regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab.