6
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In order to eliminate viral infections, hundreds of interferon-stimulated genes (ISGs) are induced via type I interferons (IFNs). However, the functions and mechanisms of most ISGs are largely unclear. A tripartite motif (TRIM) protein encoding gene TRIM69 is induced by dengue virus (DENV) infection as an ISG. TRIM69 restricts DENV replication, and its RING domain, which has the E3 ubiquitin ligase activity, is critical for its antiviral activity. An in vivo study further confirmed that TRIM69 contributes to the control of DENV infection in immunocompetent mice. Unlike many other TRIM family members, TRIM69 is not involved in modulation of IFN signaling. Instead, TRIM69 interacts with DENV Nonstructural Protein 3 (NS3) directly and mediates its polyubiquitination and degradation. Finally, Lys104 of NS3 is identified as the target of TRIM69-mediated ubiquitination. Our study demonstrates that TRIM69 restricts DENV replication by specifically ubiquitinating a viral nonstructural protein.

          Author summary

          Mosquito-borne viruses, such as Dengue virus (DENV), have become global threats to human health in recent years. However, no antiviral drugs have been approved to treat DENV induced diseases, and the safe and effective vaccines are still under development. It is of great importance to explore the detail mechanisms of host-virus interaction. In this report, we found that an interferon inducible host protein, TRIM69, is upregulated upon DENV infection. TRIM69 acts as a restriction factor for DENV replication both in vitro and in vivo. As an E3 ubiquitin ligase, TRIM69 directly binds to viral Nonstructural Protein 3 (NS3), which leads to NS3 ubiquitination and degradation. Thus TRIM69 is a novel interferon inducible host antiviral factor by targeting a specific viral protein for its degradation.

          Related collections

          Most cited references47

          • Record: found
          • Abstract: found
          • Article: not found

          An RNA cap (nucleoside-2'-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization.

          Viruses represent an attractive system with which to study the molecular basis of mRNA capping and its relation to the RNA transcription machinery. The RNA-dependent RNA polymerase NS5 of flaviviruses presents a characteristic motif of S-adenosyl-L-methionine-dependent methyltransferases at its N-terminus, and polymerase motifs at its C-terminus. The crystal structure of an N-terminal fragment of Dengue virus type 2 NS5 is reported at 2.4 A resolution. We show that this NS5 domain includes a typical methyltransferase core and exhibits a (nucleoside-2'-O-)-methyltransferase activity on capped RNA. The structure of a ternary complex comprising S-adenosyl-L-homocysteine and a guanosine triphosphate (GTP) analogue shows that 54 amino acids N-terminal to the core provide a novel GTP-binding site that selects guanine using a previously unreported mechanism. Binding studies using GTP- and RNA cap-analogues, as well as the spatial arrangement of the methyltransferase active site relative to the GTP-binding site, suggest that the latter is a specific cap-binding site. As RNA capping is an essential viral function, these results provide a structural basis for the rational design of drugs against the emerging flaviviruses.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus.

            During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The E3-ligase TRIM family of proteins regulates signaling pathways triggered by innate immune pattern-recognition receptors.

              Innate immunity conferred by the type I interferon is critical for antiviral defense. To date only a limited number of tripartite motif (TRIM) proteins have been implicated in modulation of innate immunity and anti-microbial activity. Here we report the complementary DNA cloning and systematic analysis of all known 75 human TRIMs. We demonstrate that roughly half of the 75 TRIM-family members enhanced the innate immune response and that they do this at multiple levels in signaling pathways. Moreover, messenger RNA levels and localization of most of these TRIMs were found to be altered during viral infection, suggesting that their regulatory activities are highly controlled at both pre- and posttranscriptional levels. Taken together, our data demonstrate a very considerable dedication of this large protein family to the positive regulation of the antiviral response, which supports the notion that this family of proteins evolved as a component of innate immunity. Copyright © 2013 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Role: Data curationRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Methodology
                Role: Data curationRole: Methodology
                Role: Data curationRole: Methodology
                Role: Data curationRole: Investigation
                Role: Data curationRole: Methodology
                Role: ResourcesRole: SoftwareRole: Validation
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                24 August 2018
                August 2018
                : 14
                : 8
                : e1007287
                Affiliations
                [1 ] Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, P. R. China
                [2 ] Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China
                [3 ] Department Immunology, School of Medicine, the University of Connecticut Health Center, Farmington, Connecticut, United States of America
                National Institute of Allergy and Infectious Diseases, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5117-1198
                http://orcid.org/0000-0002-1871-8390
                Article
                PPATHOGENS-D-18-00724
                10.1371/journal.ppat.1007287
                6126873
                30142214
                9febefdd-2737-42c9-b1fe-5178646638d8
                © 2018 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 April 2018
                : 16 August 2018
                Page count
                Figures: 8, Tables: 0, Pages: 24
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31500700, 31770933, and 81471571
                Award Recipient :
                Funded by: Natural Science Foundation of Colleges in Jiangsu Province
                Award ID: 17KJA310005
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: R01AI132526
                Award Recipient :
                This work was supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT), National Natural Science Foundation of China (31500700, 31770933, and 81471571), and Natural Science Foundation of Colleges in Jiangsu Province (17KJA310005). PW is supported by grant R01AI132526 from the National Institutes of Health, the United States of America. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Research and analysis methods
                Biological cultures
                Cell lines
                293T cells
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Replication
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Ubiquitination
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Flaviviruses
                Dengue Virus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Flaviviruses
                Dengue Virus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Viral Pathogens
                Flaviviruses
                Dengue Virus
                Biology and Life Sciences
                Organisms
                Viruses
                Viral Pathogens
                Flaviviruses
                Dengue Virus
                Biology and Life Sciences
                Biochemistry
                Proteins
                Interferons
                Research and Analysis Methods
                Precipitation Techniques
                Immunoprecipitation
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Ligases
                Ubiquitin Ligases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Ligases
                Ubiquitin Ligases
                Biology and Life Sciences
                Genetics
                Genetic Interference
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-09-06
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

                Comments

                Comment on this article