The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation
| Autor: | Long Yang, Peyman Nakhaei, John Hiscott, Qiang Sun, Carl F. Ware, Thibault Mesplède, Tiejun Zhao, Rongtuan Lin, Mayra Solis, Tsung-Hsien Chuang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
TRAF3
viruses Biochemistry Small hairpin RNA 0302 clinical medicine RNA Virus Infections Ubiquitin Immunology and Allergy Virology/Virulence Factors and Mechanisms Virology/Effects of Virus Infection on Host Gene Expression lcsh:QH301-705.5 0303 health sciences biology Chemistry RIG-I Intracellular Signaling Peptides and Proteins Hematology Sendai virus 3. Good health Ubiquitin ligase Cell biology RNA silencing TNF Receptor-Associated Factor 3 Virology/Immunodeficiency Viruses Phosphorylation Signal transduction Protein Binding Signal Transduction Research Article Transcriptional Activation lcsh:Immunologic diseases. Allergy Ubiquitin-Protein Ligases Immunology Virology/Immune Evasion Transfection Microbiology Virology/Emerging Viral Diseases Cell Line 03 medical and health sciences Virology Genetics Humans Molecular Biology 030304 developmental biology Adaptor Proteins Signal Transducing RNA Double-Stranded Virology/Antivirals including Modes of Action and Resistance Binding Sites biology.organism_classification Virology/Host Invasion and Cell Entry Molecular biology Immunity Innate Virology/New Therapies including Antivirals and Immunotherapy lcsh:Biology (General) biology.protein Parasitology Virology/Host Antiviral Responses lcsh:RC581-607 030215 immunology |
| Zdroj: | PLoS Pathogens, Vol 5, Iss 11, p e1000650 (2009) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | The primary role of the innate immune response is to limit the spread of infectious pathogens, with activation of Toll-like receptor (TLR) and RIG-like receptor (RLR) pathways resulting in a pro-inflammatory response required to combat infection. Limiting the activation of these signaling pathways is likewise essential to prevent tissue injury in the host. Triad3A is an E3 ubiquitin ligase that interacts with several components of TLR signaling and modulates TLR activity. In the present study, we demonstrate that Triad3A negatively regulates the RIG-I RNA sensing pathway through Lys48-linked, ubiquitin-mediated degradation of the tumor necrosis factor receptor-associated factor 3 (TRAF3) adapter. Triad3A was induced following dsRNA exposure or virus infection and decreased TRAF3 levels in a dose-dependent manner; moreover, Triad3A expression blocked IRF-3 activation by Ser-396 phosphorylation and inhibited the expression of type 1 interferon and antiviral genes. Lys48-linked ubiquitination of TRAF3 by Triad3A increased TRAF3 turnover, whereas reduction of Triad3A expression by stable shRNA expression correlated with an increase in TRAF3 protein expression and enhancement of the antiviral response following VSV or Sendai virus infection. Triad3A and TRAF3 physically interacted together, and TRAF3 residues Y440 and Q442—previously shown to be important for association with the MAVS adapter—were also critical for Triad3A. Point mutation of the TRAF-Interacting-Motif (TIM) of Triad3A abrogated its ability to interact with TRAF3 and modulate RIG-I signaling. TRAF3 appears to undergo sequential ubiquitin “immuno-editing” following virus infection that is crucial for regulation of RIG-I-dependent signaling to the antiviral response. Thus, Triad3A represents a versatile E3 ubiquitin ligase that negatively regulates RIG-like receptor signaling by targeting TRAF3 for degradation following RNA virus infection. Author Summary RNA virus infection is detected through TLR-dependent and TLR-independent mechanisms. Early viral replicative intermediates are detected by two recently characterized cystolic viral RNA receptors, RIG-I and MDA-5, leading to the production of pro-inflammatory cytokines and type I interferons (IFNs). Dysfunctional responses, either failure to respond or hyper-responsiveness, may lead to both acute and chronic immunodeficiency and inflammatory diseases. Thus, the intensity and duration of RLR signaling must be tightly controlled. One general mechanism by which innate immune receptors and their downstream adapters are regulated involves protein degradation mediated by the ubiquitination pathway. Our study demonstrates that the E3 ubiquitin ligase Triad3A negatively regulates the RIG-I-like receptor pathway by targeting the adapter molecule TRAF3 for proteasomal degradation through Lys48-linked ubiquitin-mediated degradation. Thus, Triad3A represents a key molecule involved in the negative regulation of the host antiviral response triggered by RNA virus infection. |
| Databáze: | OpenAIRE |
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