RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses
The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a...
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Published in | Immunology and cell biology Vol. 97; no. 9; p. 840 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.10.2019
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Abstract | The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field. |
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AbstractList | The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field. |
Author | Hansbro, Philip M Hsu, Alan C Tate, Michelle D Kedzierski, Lukasz Masters, Seth L Nicholson, Sandra E Nicola, Nicos A Kolesnik, Tatiana B Willemsen, Joschka Hayman, Thomas J Dagley, Laura F Wark, Peter A Baker, Paul J Belz, Gabrielle T Kershaw, Nadia J Webb, Andrew I Kedzierska, Katherine Binder, Marco |
Author_xml | – sequence: 1 givenname: Thomas J surname: Hayman fullname: Hayman, Thomas J organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 2 givenname: Alan C orcidid: 0000-0002-6640-0846 surname: Hsu fullname: Hsu, Alan C organization: Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia – sequence: 3 givenname: Tatiana B surname: Kolesnik fullname: Kolesnik, Tatiana B organization: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia – sequence: 4 givenname: Laura F surname: Dagley fullname: Dagley, Laura F organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 5 givenname: Joschka surname: Willemsen fullname: Willemsen, Joschka organization: Research Group Dynamics of Early Viral Infection and the Innate Antiviral Response, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 6 givenname: Michelle D surname: Tate fullname: Tate, Michelle D organization: Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia – sequence: 7 givenname: Paul J surname: Baker fullname: Baker, Paul J organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 8 givenname: Nadia J surname: Kershaw fullname: Kershaw, Nadia J organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 9 givenname: Lukasz surname: Kedzierski fullname: Kedzierski, Lukasz organization: Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia – sequence: 10 givenname: Andrew I surname: Webb fullname: Webb, Andrew I organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 11 givenname: Peter A surname: Wark fullname: Wark, Peter A organization: Centre for Inflammation, Centenary Institute, The University of Technology Sydney, Sydney, NSW, Australia – sequence: 12 givenname: Katherine orcidid: 0000-0001-6141-335X surname: Kedzierska fullname: Kedzierska, Katherine organization: Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia – sequence: 13 givenname: Seth L surname: Masters fullname: Masters, Seth L organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 14 givenname: Gabrielle T surname: Belz fullname: Belz, Gabrielle T organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 15 givenname: Marco surname: Binder fullname: Binder, Marco organization: Research Group Dynamics of Early Viral Infection and the Innate Antiviral Response, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany – sequence: 16 givenname: Philip M surname: Hansbro fullname: Hansbro, Philip M organization: Centre for Inflammation, Centenary Institute, The University of Technology Sydney, Sydney, NSW, Australia – sequence: 17 givenname: Nicos A surname: Nicola fullname: Nicola, Nicos A organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia – sequence: 18 givenname: Sandra E surname: Nicholson fullname: Nicholson, Sandra E organization: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia |
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SubjectTerms | A549 Cells Animals Antiviral Agents - metabolism Cell Line DEAD Box Protein 58 - metabolism DNA-Binding Proteins - metabolism Epithelial Cells - microbiology Epithelial Cells - virology Gene Deletion Humans Ligands Mice, Inbred C57BL Receptors, Immunologic RNA - metabolism Signal Transduction Transcription Factors - metabolism Tripartite Motif Proteins - metabolism Ubiquitin-Protein Ligases - metabolism |
Title | RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses |
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