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TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3
Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerizatio...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357427/ https://www.ncbi.nlm.nih.gov/pubmed/25763818 http://dx.doi.org/10.1371/journal.ppat.1004726 |
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author | Wang, Peng Zhao, Wei Zhao, Kai Zhang, Lei Gao, Chengjiang |
author_facet | Wang, Peng Zhao, Wei Zhao, Kai Zhang, Lei Gao, Chengjiang |
author_sort | Wang, Peng |
collection | PubMed |
description | Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear translocation. However, the mechanisms for the termination of IRF3 activation in nucleus are elusive. Here we report the identification of TRIM26 to negatively regulate IFN-β production and antiviral response by targeting nuclear IRF3. TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. TRIM26 degraded WT IRF3 and the constitutive active mutant IRF3 5D, but not the phosphorylation deficient mutant IRF3 5A. Furthermore, IRF3 mutant in the Nuclear Localization Signal (NLS), which could not move into nucleus, was not degraded by TRIM26. Importantly, virus infection promoted TRIM26 nuclear translocation, which was required for IRF3 degradation. As a consequence, TRIM26 attenuated IFN-β promoter activation and IFN-β production downstream of TLR3/4, RLR and DNA sensing pathways. TRIM26 transgenic mice showed much less IRF3 activation and IFN-β production, while increased virus replication. Our findings delineate a novel mechanism for the termination of IRF3 activation in nucleus through TRIM26-mediated IRF3 ubiquitination and degradation. |
format | Online Article Text |
id | pubmed-4357427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43574272015-03-23 TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 Wang, Peng Zhao, Wei Zhao, Kai Zhang, Lei Gao, Chengjiang PLoS Pathog Research Article Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear translocation. However, the mechanisms for the termination of IRF3 activation in nucleus are elusive. Here we report the identification of TRIM26 to negatively regulate IFN-β production and antiviral response by targeting nuclear IRF3. TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. TRIM26 degraded WT IRF3 and the constitutive active mutant IRF3 5D, but not the phosphorylation deficient mutant IRF3 5A. Furthermore, IRF3 mutant in the Nuclear Localization Signal (NLS), which could not move into nucleus, was not degraded by TRIM26. Importantly, virus infection promoted TRIM26 nuclear translocation, which was required for IRF3 degradation. As a consequence, TRIM26 attenuated IFN-β promoter activation and IFN-β production downstream of TLR3/4, RLR and DNA sensing pathways. TRIM26 transgenic mice showed much less IRF3 activation and IFN-β production, while increased virus replication. Our findings delineate a novel mechanism for the termination of IRF3 activation in nucleus through TRIM26-mediated IRF3 ubiquitination and degradation. Public Library of Science 2015-03-12 /pmc/articles/PMC4357427/ /pubmed/25763818 http://dx.doi.org/10.1371/journal.ppat.1004726 Text en © 2015 Wang et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Wang, Peng Zhao, Wei Zhao, Kai Zhang, Lei Gao, Chengjiang TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title_full | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title_fullStr | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title_full_unstemmed | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title_short | TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3 |
title_sort | trim26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear irf3 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357427/ https://www.ncbi.nlm.nih.gov/pubmed/25763818 http://dx.doi.org/10.1371/journal.ppat.1004726 |
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