TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3

PLoS Pathog. 2015 Mar 12;11(3):e1004726. doi: 10.1371/journal.ppat.1004726. eCollection 2015 Mar.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Nucleus / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescent Antibody Technique
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon-beta / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rhabdoviridae Infections / immunology
  • Rhabdoviridae Infections / metabolism*
  • Transfection
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Vesiculovirus

Substances

  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Tripartite Motif Proteins
  • Interferon-beta
  • Trim26 protein, mouse
  • Ubiquitin-Protein Ligases

Grant support

This work was supported in part by grants from the National Natural Science Foundation of China (81172813, 81273219), the Shandong Provincial Nature Science Foundation for Distinguished Young Scholars (JQ201120), and the Specialized Research Fund for the Doctoral Program of Higher Education of China (20130131130010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.