Interferon-Inducible Antiviral Effectors

Total Page:16

File Type:pdf, Size:1020Kb

Interferon-Inducible Antiviral Effectors REVIEWS Interferon-inducible antiviral effectors Anthony J. Sadler and Bryan R. G. Williams Abstract | Since the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and their antiviral activities. Gene targeting studies have distinguished four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2′,5′-oligoadenylate-synthetase-directed ribonuclease L pathway, the protein kinase R pathway and the ISG15 ubiquitin-like pathway. As discussed in this Review, these effector pathways individually block viral transcription, degrade viral RNA, inhibit translation and modify protein function to control all steps of viral replication. Ongoing research continues to expose additional activities for these effector proteins and has revealed unanticipated functions of the antiviral response. Pattern-recognition Interferon (IFN) was discovered more than 50 years ago in components of the IFNR signalling pathway (STAT1 receptors as an agent that inhibited the replication of influenza (signal transducer and activator of transcription 1), TYK2 (PRRs). Host receptors that can virus1. The IFN family of cytokines is now recognized as (tyrosine kinase 2) or UNC93B) die of viral disease, with sense pathogen-associated a key component of the innate immune response and the the defect in IFNAR (rather than IFNGR) signalling molecular patterns and initiate 6–9 signalling cascades that lead to first line of defence against viral infection. Accordingly, having the more significant role . an innate immune response. IFNs are currently used therapeutically, with the most The binding of type I IFNs to the IFNAR initiates a These can be membrane bound noteworthy example being the treatment of hepatitis C signalling cascade, which leads to the induction of more (such as Toll-like receptors) or virus (HCV) infection, and they are also used against than 300 IFN-stimulated genes (ISGs)10. However, rela- soluble cytoplasmic receptors various other disorders, including numerous malignancies tively few of these ISGs have been directly implicated in (such as RIG‑I, MDA5 and REF. 2 NLRs). and multiple sclerosis (reviewed in ). instigating the antiviral state. Instead, many of the gene Three classes of IFN have been identified, designated products encode pattern-recognition receptors (PRRs) that GTPase types I to III, and are classified according to the receptor detect viral molecules and modulate signalling pathways, A signalling protein that binds complex they signal through (FIG. 1). The type II class of or transcription factors that form an amplification loop guanine nucleotides. A GTPase γ is active in the GTP-bound IFN comprises the single IFN gene product that binds resulting in increased IFN production and protection state and is inactivated when it the IFNγ receptor (IFNGR) complex, and mediates broad from virus spread to limit disease. Nevertheless, some ISGs hydrolyses GTP into GDP. immune responses to pathogens other than viruses. The encode proteins with potential for direct antiviral activity, more recently described type III IFNs include three IFNλ including proteins that catalyse cytoskeletal remodelling, gene products that signal through receptors containing that induce apoptosis, that regulate post-transcriptional IFNLR1 (IFNλ receptor 1; also known as IL-28Ra) and events (splicing, mRNA editing, RNA degradation and the IL‑10R2 (also known as IL-10Rβ). So far, little is known multiple steps of protein translation) and proteins that are about the type III IFNs, although they are known to involved in subsequent post-translational modification. regulate the antiviral response and have been proposed Indeed, several such proteins, ISG15 (IFN-stimulated pro- to be the ancestral type I IFNs3. Type I IFNs, which in tein of 15 kDa), the GTPase Mx1 (myxovirus resistance 1), humans comprise 13 IFNα subtypes, IFNβ, IFNκ, IFNε, ribonuclease L (RNaseL) and protein kinase R (PKR; also IFNο, IFNτ and IFNδ, engage the ubiquitously expressed known as EIF2αK2), have been shown to function as α Monash Institute of Medical IFNAR (IFN receptor) complex that is composed of antiviral effectors in studies of knockout mice. Mice Research, Monash University, IFNAR1 and IFNAR2. The function of type I IFNs is with mutations or deficiencies in key steps of the path- Clayton, Victoria 3168, well characterized and they are known to be essential ways that are triggered by these proteins have increased Australia for mounting a robust host response against viral infec- susceptibility to viral infection. Correspondence to B.R.G.W. tion. Accordingly, IFNAR-deficient mice have increased In this Review, we summarize our current under- e-mail: bryan.williams@med. susceptibility to numerous viruses but maintain resist- standing of the role of ISG15, Mx1, RNaseL and PKR in monash.edu.au ance to other microbial pathogens, such as Listeria the antiviral host immune response. However, although doi:10.1038/nri2314 monocytogenes4,5. Similarly, humans with genetic defects these four proteins are known to be important in the nature revieWs | IMMUNOLOGY vOlume 8 | July 2008 | 559 © 2008 Macmillan Publishers Limited. All rights reserved. REVIEWS Type I IFNType III IFN Type II IFN ISG15, the Mx proteins, the 2′,5′-oligoadenylate syn- IFNAR1 IFNAR2 thetase (OAS)-directed RNaseL pathway and PKR have varying responsiveness to type I IFNs: ISG15 is one of the Plasma most highly induced ISGs and, when coupled to protein IL-10R2 IFNLR1 IFNGR2 IFNGR1 membrane substrates, it modulates numerous cellular activities; Mx Cytoplasm proteins are also highly induced by type I IFNs and then TYK2 JAK1 TYK2 JAK1 JAK2 JA JAK2 K assemble into oligomers that are constitutively active; 1 JAK1 OAS proteins are expressed at low levels in unstimulated cells, and are considerably induced by type I IFNs pro- 2 1 1 duced in response to viral RNA; and PKR is constitutively P TAT TAT P TAT P expressed as an inactive kinase that is activated by viral S S S RNA, then further upregulated by type I IFNs. This vari- able responsiveness to IFN also underlies the function of each protein as solely an IFN effector, or as PRRs to 2 1 1 1 P P GAF enhance the IFN response. TAT TAT TAT P TAT P S S S ISGF3 S IRF9 ISG15 One of the most prominent ISGs to be induced during Nucleus viral infection and the ensuing type I IFN response is 2 1 the ~15 kDa protein ISG15. Although the ISG15 gene 1 1 P P was cloned over 20 years ago12, an antiviral function of TAT TAT TAT P TAT P S S S ISG15, Mx, S the encoded protein has only recently been established IRF9 OAS and GAS and considerable work is still required to detail all of its PKR ISRE Antimycobacterial actions and to resolve contradictory findings. immunity ISG15 was identified soon after the landmark dis- Antiviral immunity covery of ubiquitin, and was immediately recognized as Figure 1 | Interferon receptor signalling. The action of the interferons (IFNs) is a ubiquitin homologue13 (FIG. 2). Protein ubiquitylation mediated through three receptor complexes: a heterodimer of IFNα receptor 1 (IFNAR1) regulates many aspects of the innate immune response, Nature Reviews | Immunology and IFNAR2 binds type I IFNs; the interleukin‑10 receptor 2 (IL‑10R2) associates with including intracellular signal transduction (for example, IFNLR1 (IFNλ receptor 1) to bind the three IFNλ subtypes; and a tetramer consisting of the activation of nuclear factor-κB (NF-κB)), and func- two IFNGR2 (IFNγ receptor 2) chains and two IFNGR1 chains binds dimers of the type II tions of the adaptive immune system, such as initiating IFNγ. Following binding by type I IFNs, signal transduction is initiated by pre-associated tolerance (reviewed in REF.14). Given the importance of tyrosine kinases (JAK1 and TYK2 (tyrosine kinase 2)), which phosphorylate IFNAR1 and leads to the recruitment and phosphorylation of the signal transducers and activators ubiquitylation in the immune response, it is perhaps not of transcription (STATs). STAT heterodimers associate with IFN-regulatory factor 9 (IRF9) surprising that there is an IFN-regulated ubiquitin-like to form IFN-stimulated gene factor 3 (ISGF3), or STAT homodimers to form the IFNγ protein response. This response, as mediated by ISGs, activation factor (GAF). These complexes translocate to the nucleus to induce is referred to as ISGylation. IFN-stimulated genes from IFN-stimulated response elements (ISREs) or GAS promoter ISG15 is expressed as a 165 amino-acid precursor elements, for type I and type III, or type II IFN responses, respectively. Divergence from that is subsequently processed to expose the C‑terminal this simplified signalling pathway can occur, for example, type I IFNs are reported to elicit sequence LRLRGG. The equivalent diglycine residues STAT homodimers, and more complicated interplay, with activation of other STAT within this motif in ubiquitin are adenylated and con- proteins, occurs than is shown here. ISG15, IFN-stimulated protein of 15 kDa; Mx, jugated by a thiolester bond to cysteine residues of myxovirus resistance; OAS, 2',5'-oligoadenylate synthetase; PKR, protein kinase R. three enzymes, a ubiquitin‑activating enzyme (E1), a ubiquitin‑conjugating enzyme (E2) and a ubiquitin antiviral response, they do not represent the complete ligase enzyme (E3), before being transferred to lysine repertoire of antiviral effectors. Additional ISGs that residues on protein substrates. As the ubiquitin E1 probably
Recommended publications
  • Ribonuclease L Mediates the Cell-Lethal Phenotype of the Double-Stranded RNA Editing
    1 2 Ribonuclease L mediates the cell-lethal phenotype of the double-stranded RNA editing 3 enzyme ADAR1 in a human cell line 4 5 Yize Lia,#, Shuvojit Banerjeeb,#, Stephen A. Goldsteina, Beihua Dongb, Christina Gaughanb, Sneha 6 Rathc, Jesse Donovanc, Alexei Korennykhc, Robert H. Silvermanb,* and Susan R Weissa,* 7 aDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, 8 Philadelphia, PA, USA, 19104; b Department of Cancer Biology, Lerner Research Institute, 9 Cleveland Clinic, Cleveland, OH, USA 44195; c Department of Molecular Biology, Princeton 10 University, Princeton, NJ 08544 11 12 13 14 15 16 17 18 # These authors contributed equally to this work 19 * Corresponding authors 20 21 22 23 24 25 26 27 28 29 30 Abstract 31 ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA 32 reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental 33 and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are 34 embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN 35 induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of 36 ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human 37 lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or 38 by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result 39 demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the 40 presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway 41 for endogenous dsRNA that leads to cell death.
    [Show full text]
  • Transcriptomic Profiling of Equine and Viral Genes in Peripheral Blood
    pathogens Article Transcriptomic Profiling of Equine and Viral Genes in Peripheral Blood Mononuclear Cells in Horses during Equine Herpesvirus 1 Infection Lila M. Zarski 1, Patty Sue D. Weber 2, Yao Lee 1 and Gisela Soboll Hussey 1,* 1 Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA; [email protected] (L.M.Z.); [email protected] (Y.L.) 2 Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI 48824, USA; [email protected] * Correspondence: [email protected] Abstract: Equine herpesvirus 1 (EHV-1) affects horses worldwide and causes respiratory dis- ease, abortions, and equine herpesvirus myeloencephalopathy (EHM). Following infection, a cell- associated viremia is established in the peripheral blood mononuclear cells (PBMCs). This viremia is essential for transport of EHV-1 to secondary infection sites where subsequent immunopathol- ogy results in diseases such as abortion or EHM. Because of the central role of PBMCs in EHV-1 pathogenesis, our goal was to establish a gene expression analysis of host and equine herpesvirus genes during EHV-1 viremia using RNA sequencing. When comparing transcriptomes of PBMCs during peak viremia to those prior to EHV-1 infection, we found 51 differentially expressed equine genes (48 upregulated and 3 downregulated). After gene ontology analysis, processes such as the interferon defense response, response to chemokines, the complement protein activation cascade, cell adhesion, and coagulation were overrepresented during viremia. Additionally, transcripts for EHV-1, EHV-2, and EHV-5 were identified in pre- and post-EHV-1-infection samples. Looking at Citation: Zarski, L.M.; Weber, P.S.D.; micro RNAs (miRNAs), 278 known equine miRNAs and 855 potentially novel equine miRNAs were Lee, Y.; Soboll Hussey, G.
    [Show full text]
  • Identification and Classification of Differentially Expressed Genes
    Informatics in Medicine Unlocked 20 (2020) 100384 Contents lists available at ScienceDirect Informatics in Medicine Unlocked journal homepage: http://www.elsevier.com/locate/imu Identification and classification of differentially expressed genes reveal potential molecular signature associated with SARS-CoV-2 infection in lung adenocarcinomal cells Opeyemi S. Soremekun, Kehinde F. Omolabi, Mahmoud E.S. Soliman * Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa ARTICLE INFO ABSTRACT Keywords: Genomic techniques such as next-generation sequencing and microarrays have facilitated the identification and Differentially expressed genes classification of molecular signatures inherent in cells upon viral infection, for possible therapeutic targets. SARS-CoV-2 Therefore, in this study, we performed a differential gene expression analysis, pathway enrichment analysis, and COVID-19 gene ontology on RNAseq data obtained from SARS-CoV-2 infected A549 cells. Differential expression analysis Enrichment analysis revealed that 753 genes were up-regulated while 746 down-regulated. SNORA81, OAS2, SYCP2, LOC100506985, RNAseq and SNORD35B are the top 5 upregulated genes upon SARS-Cov-2 infection. Expectedly, these genes have been implicated in the immune response to viral assaults. In the Ontology of protein classification, a high percentage of the genes are classified as Gene-specific transcriptional regulator, metabolite interconversion enzyme, and Protein modifying enzymes. Twenty pathways with P-value lower than 0.05 were enriched in the up-regulated genes while 18 pathways are enriched in the down-regulated DEGs. The toll-like receptor signalling pathway is one of the major pathways enriched. This pathway plays an important role in the innate immune system by identifying the pathogen-associated molecular signature emanating from various microorganisms.
    [Show full text]
  • A Genetic Variant Protective Against Severe COVID-19 Is Inherited from Neandertals
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.05.327197; this version posted October 9, 2020. 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 4.0 International license. A genetic variant protective against severe COVID-19 is inherited from Neandertals Authors Hugo Zeberg1,2* and Svante Pääbo1,3* Affiliations 1 Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany. 2 Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden. 3 Okinawa Institute of Science and Technology, Onna-son, Okinawa 904-0495, Japan. *Corresponding authors: [email protected], [email protected] Abstract It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome- wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.05.327197; this version posted October 9, 2020.
    [Show full text]
  • Mir-125 in Normal and Malignant Hematopoiesis
    Leukemia (2012) 26, 2011–2018 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu SPOTLIGHT REVIEW MiR-125 in normal and malignant hematopoiesis L Shaham1,2, V Binder3,4,NGefen1,5, A Borkhardt3 and S Izraeli1,5 MiR-125 is a highly conserved microRNA throughout many different species from nematode to humans. In humans, there are three homologs (hsa-miR-125b-1, hsa-miR-125b-2 and hsa-miR-125a). Here we review a recent research on the role of miR-125 in normal and malignant hematopoietic cells. Its high expression in hematopoietic stem cells (HSCs) enhances self-renewal and survival. Its expression in specific subtypes of myeloid and lymphoid leukemias provides resistance to apoptosis and blocks further differentiation. A direct oncogenic role in the hematopoietic system has recently been demonstrated by several mouse models. Targets of miR-125b include key proteins regulating apoptosis, innate immunity, inflammation and hematopoietic differentiation. Leukemia (2012) 26, 2011–2018; doi:10.1038/leu.2012.90 Keywords: microRNA; hematopoiesis; hematological malignancies; acute myeloid leukemia; acute lymphoblastic leukemia MicroRNAs (miRNAs) are 21–23-nucleotide non-coding RNAs that nucleotides with the seed region of miR-125b (ebv-miR-BART21-5p, have crucial roles in fundamental biological processes by ebv-miR-BART8 and rlcv-miR-rL1-25). In humans, as in most of the regulating the levels of multiple proteins. They are transcribed genomes, there are two paralogs (hsa-miR-125b-1 on chromosome as primary miRNAs and processed in the nucleus by the RNase III 11 and hsa-miR-125b-2 on chromosome 21), coding for the same endonuclease DROSHA to liberate 70-nucleotide stem loops, the mature sequence.
    [Show full text]
  • Environmental Influences on Endothelial Gene Expression
    ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community.
    [Show full text]
  • Interactions Between Protein Kinase R Activity, Rnase L Cleavage and Elastase Activity, and Their Clinical Relevance
    in vivo 22: 115-122 (2008) Unravelling Intracellular Immune Dysfunctions in Chronic Fatigue Syndrome: Interactions between Protein Kinase R Activity, RNase L Cleavage and Elastase Activity, and their Clinical Relevance MIRA MEEUS1,2, JO NIJS1,2, NEIL MCGREGOR3, ROMAIN MEEUSEN1, GUY DE SCHUTTER1, STEVEN TRUIJEN2, MARC FRÉMONT4, ELKE VAN HOOF1 and KENNY DE MEIRLEIR1 1Department of Human Physiology, Faculty of Physical Education and Physiotherapy; Vrije Universiteit Brussel (VUB); 2Division of Musculoskeletal Physiotherapy, Department of Health Sciences, University College Antwerp (HA), Belgium; 3Bio21, Institute of Biomedical Research, University of Melbourne, Parksville, Victoria 3000, Australia; 4RED Laboratories, Pontbeek 61, 1731 Zellik, Belgium Abstract. This study examined possible interactions between the 1994 definition of the Centre for Disease Control and immunological abnormalities and symptoms in CFS. Sixteen Prevention (CDCP) (2), besides severe fatigue, a CFS CFS patients filled in a battery of questionnaires, evaluating patient presents a number of other symptoms, such as daily functioning, and underwent venous blood sampling, in myalgia, arthralgia, low-grade fever, concentration order to analyse immunological abnormalities. Ribonuclease difficulties. Because CFS is often preceded by viral episodes (RNase) L cleavage was associated with RNase L activity (3, 4) or negative, stressful life events (5), it is possible that (rs=0.570; p=0.021), protein kinase R (PKR) (rs=0.716; infectious agents and environmental factors trigger p=0.002) and elastase activity (rs=0.500; p=0.049). RNase persistent immunological dysregulations. L activity was related to elastase (rs=0.547; p=0.028) and Two intracellular immune dysregulations are widely PKR activity (rs=0.625; p=0.010).
    [Show full text]
  • The Zinc-Finger Antiviral Protein Recruits the RNA Processing Exosome to Degrade the Target Mrna
    The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA Xuemin Guo, Jing Ma, Jing Sun, and Guangxia Gao* Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved November 3, 2006 (received for review August 14, 2006) Zinc-finger antiviral protein (ZAP) is a host antiviral factor that putative RNA helicase (Kiaa0052), and a protein that is specifically specifically inhibits the replication of Moloney murine leukemia phosphorylated in the M phase of the cell cycle (Mpp6) (36, 38). virus (MLV) and Sindbis virus (SIN) by preventing accumulation of The RNase-PH domain subunits and the S1/KH RNA-binding the viral mRNA in the cytoplasm. In previous studies, we demon- domain subunits are considered to be the core components of the strated that ZAP directly binds to its specific target mRNAs. In this exosome, whereas Kiaa0052 and Mpp6 are considered to be article, we provide evidence indicating that ZAP recruits the RNA accessory factors (36, 38). Yeast PM/Scl-100 is found only in the processing exosome to degrade the target RNA. ZAP comigrated nuclear exosome (36, 46). with the exosome in sucrose or glycerol velocity gradient centrif- The structure of the exosome is not yet determined. Based on the ugation. Immunoprecipitation of ZAP coprecipitated the exosome results of mammalian-two-hybrid and yeast-two-hybrid experi- components. In vitro pull-down assays indicated that ZAP directly ments (38, 56–59), the six RNase-PH domain-containing subunits interacted with the exosome component hRrp46p and that the are thought to assemble into a doughnut-shaped ring.
    [Show full text]
  • Oligoadenylate Synthetase (OAS) Proteins
    bioRxiv preprint doi: https://doi.org/10.1101/804716; this version posted October 15, 2019. 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. In silico identification of potential inhibitors against human 2’-5’- oligoadenylate synthetase (OAS) proteins Karen J. Gonzalez1, Diego Moncada-Giraldo1, Juan B. Gutierrez2* 1Institute of Bioinformatics, University of Georgia; 2Department of Mathematics, University of Texas at San Antonio. * [email protected] Abstract As part of the type I IFN signaling, the 2’-5’- oligoadenylate synthetase (OAS) proteins have been involved in the progression of several non-viral diseases. Notably, OAS has been correlated with immune-modulatory functions that promote chronic inflammatory conditions, autoimmune disorders, cancer, and infectious diseases. In spite of this, OAS enzymes have been ignored as drug targets, and to date, there are no reports of compounds that can inhibit their activity. In this study, we have used homology modeling and virtual high-throughput screening to identify potential inhibitors of the human proteins OAS1, OAS2, and OAS3. Altogether, we have found 37 molecules that could exert a competitive inhibition in the ATP binding sites of OAS proteins, independently of the activation state of the enzyme. This latter characteristic, which might be crucial for a versatile inhibitor, was observed in compounds interacting with the residues Asp75, Asp77, Gln229, and Tyr230 in OAS1, and their equivalents in OAS2 and OAS3. Although there was little correlation between specific chemical fragments and particular interactions, intermolecular contacts with OAS catalytic triad and other critical amino acids were mainly promoted by heterocycles with π electrons and hydrogen bond acceptors.
    [Show full text]
  • High Transdominant Revm10 Protein Levels Are Required to Inhibit HIV-1 Replication in Cell Lines and Primary T Cells: Implication for Gene Therapy of AIDS
    Gene Therapy (1997) 4, 128–139 1997 Stockton Press All rights reserved 0969-7128/97 $12.00 High transdominant RevM10 protein levels are required to inhibit HIV-1 replication in cell lines and primary T cells: implication for gene therapy of AIDS I Plavec1, M Agarwal1,KEHo2, M Pineda1, J Auten1, J Baker1, H Matsuzaki3, S Escaich4, M Bonyhadi1 and E Bo¨ hnlein1 1Progenesys Program, SyStemix Inc, 3155 Porter Drive, Palo Alto, CA 94304, USA Expression of antiviral genes in CD4+ T cells has been pro- uniformly higher than from internal promoters (eg CMV, posed as a strategy for gene therapy of AIDS. Over the PGK). Analysis of selected vectors in acutely and chron- past years, we and others have developed retroviral vec- ically HIV-infected cell lines suggested that threshold levels tors encoding the RevM10 protein, a dominant-negative of RevM10 expression are required to achieve inhibition of mutant of the HIV-1 Rev trans-activator protein. We could HIV replication. LTR-driven RevM10 expression also demonstrate gene transfer and inhibition of HIV-1 repli- yielded high steady-state protein levels in activated primary cation in cultured T cell lines and primary T cells. However, T cells resulting in inhibition of HIV replication, and there little is known about the levels of the antiviral protein was no apparent difference between the MoMLV, MPSV required to achieve a therapeutic effect, particularly in pri- and MESV-LTR vectors. However, RevM10 expression mary cells. In this report, we compare different vector was down-regulated in resting primary cells and conse- designs with regard to expression of the antiviral gene to quently anti-HIV efficacy was significantly reduced.
    [Show full text]
  • Oas1b-Dependent Immune Transcriptional Profiles of West Nile
    MULTIPARENTAL POPULATIONS Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross Richard Green,*,† Courtney Wilkins,*,† Sunil Thomas,*,† Aimee Sekine,*,† Duncan M. Hendrick,*,† Kathleen Voss,*,† Renee C. Ireton,*,† Michael Mooney,‡,§ Jennifer T. Go,*,† Gabrielle Choonoo,‡,§ Sophia Jeng,** Fernando Pardo-Manuel de Villena,††,‡‡ Martin T. Ferris,†† Shannon McWeeney,‡,§,** and Michael Gale Jr.*,†,1 *Department of Immunology and †Center for Innate Immunity and Immune Disease (CIIID), University of Washington, § Seattle, Washington 98109, ‡OHSU Knight Cancer Institute, Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, and **Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239, ††Department of Genetics and ‡‡Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27514 ABSTRACT The oligoadenylate-synthetase (Oas) gene locus provides innate immune resistance to virus KEYWORDS infection. In mouse models, variation in the Oas1b gene influences host susceptibility to flavivirus infection. Oas However, the impact of Oas variation on overall innate immune programming and global gene expression flavivirus among tissues and in different genetic backgrounds has not been defined. We examined how Oas1b acts viral infection in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of innate immunity genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, multiparental 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective Oas1b, whereas the three populations wild-derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full-length OAS1B pro- Multi-parent tein.
    [Show full text]
  • Identification of Sequence Variants
    Wang et al. BMC Medical Genomics (2019) 12:28 https://doi.org/10.1186/s12920-019-0475-x RESEARCH ARTICLE Open Access Identification of sequence variants associated with severe microtia-astresia by targeted sequencing Pu Wang1, Yibei Wang1, Xinmiao Fan1, Yaping Liu2, Yue Fan1, Tao Liu3, Chongjian Chen3, Shuyang Zhang4*† and Xiaowei Chen1*† Abstract Background: Microtia-atresia is characterized by abnormalities of the auricle (microtia) and aplasia or hypoplasia of the external auditory canal, often associated with middle ear abnormalities. To date, no causal genetic mutations or genes have been identified in microtia-atresia patients. Methods: We designed a panel of 131 genes associated with external/middle or inner ear deformity. Targeted genomic capturing combined with next-generation sequencing (NGS) was utilized to screen for mutations in 40 severe microtia-atresia patients. Mutations detected by NGS were filtered and validated. And then mutations were divided into three categories—rare or novel variants, low-frequency variants and common variants—based on their frequency in the public database. The rare or novel mutations were prioritized by pathogenicity analysis. For the low-frequency variants and common variants, we used association studies to explore risk factors of severe microtia-atresia. Results: Sixty-five rare heterozygous mutations of 42 genes were identified in 27 (67.5%) severe microtia-atresia patients. Association studies to determine genes that were potentially pathogenic found that PLEC, USH2A, FREM2, DCHS1, GLI3, POMT1 and GBA genes were significantly associated with severe microtia-atresia. Of these, DCHS1 was strongly suggested to cause severe microtia-atresia as it was identified by both low-frequency and common variants association studies.
    [Show full text]