Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors.

Hdl Handle:
http://hdl.handle.net/10147/115726
Title:
Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors.
Authors:
Higgs, Rowan; Lazzari, Elisa; Wynne, Claire; Ní Gabhann, Joan; Espinosa, Alexander; Wahren-Herlenius, Marie; Jefferies, Caroline A
Affiliation:
Molecular and Cellular Therapeutics and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
Citation:
Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. 2010, 5 (7):e11776 PLoS ONE
Journal:
PloS one
Issue Date:
2010
URI:
http://hdl.handle.net/10147/115726
DOI:
10.1371/journal.pone.0011776
PubMed ID:
20668674
Abstract:
Ro52 is a member of the TRIM family of single-protein E3 ligases and is also a target for autoantibody production in systemic lupus erythematosus and Sjögren's syndrome. We previously demonstrated a novel function of Ro52 in the ubiquitination and proteasomal degradation of IRF3 following TLR3/4 stimulation. We now present evidence that Ro52 has a similar role in regulating the stability and activity of IRF7. Endogenous immunoprecipitation of Ro52-bound proteins revealed that IRF7 associates with Ro52, an effect which increases following TLR7 and TLR9 stimulation, suggesting that Ro52 interacts with IRF7 post-pathogen recognition. Furthermore, we show that Ro52 ubiquitinates IRF7 in a dose-dependent manner, resulting in a decrease in total IRF7 expression and a subsequent decrease in IFN-alpha production. IRF7 stability was increased in bone marrow-derived macrophages from Ro52-deficient mice stimulated with imiquimod or CpG-B, consistent with a role for Ro52 in the negative regulation of IRF7 signalling. Taken together, these results suggest that Ro52-mediated ubiquitination promotes the degradation of IRF7 following TLR7 and TLR9 stimulation. As Ro52 is known to be IFN-inducible, this system constitutes a negative-feedback loop that acts to protect the host from the prolonged activation of the immune response.
Item Type:
Article
Language:
en
Keywords:
IMMUNE SYSTEM; GENETICS
MeSH:
Animals; Cell Line; Hela Cells; Humans; Immunoprecipitation; Interferon Regulatory Factor-7; Interferon-alpha; Mice; Mice, Knockout; Protein Binding; Ribonucleoproteins; Toll-Like Receptor 7; Toll-Like Receptor 9; Toll-Like Receptors; Ubiquitination
ISSN:
1932-6203

Full metadata record

DC FieldValue Language
dc.contributor.authorHiggs, Rowanen
dc.contributor.authorLazzari, Elisaen
dc.contributor.authorWynne, Claireen
dc.contributor.authorNí Gabhann, Joanen
dc.contributor.authorEspinosa, Alexanderen
dc.contributor.authorWahren-Herlenius, Marieen
dc.contributor.authorJefferies, Caroline Aen
dc.date.accessioned2010-11-17T12:46:59Z-
dc.date.available2010-11-17T12:46:59Z-
dc.date.issued2010-
dc.identifier.citationSelf protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. 2010, 5 (7):e11776 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid20668674-
dc.identifier.doi10.1371/journal.pone.0011776-
dc.identifier.urihttp://hdl.handle.net/10147/115726-
dc.description.abstractRo52 is a member of the TRIM family of single-protein E3 ligases and is also a target for autoantibody production in systemic lupus erythematosus and Sjögren's syndrome. We previously demonstrated a novel function of Ro52 in the ubiquitination and proteasomal degradation of IRF3 following TLR3/4 stimulation. We now present evidence that Ro52 has a similar role in regulating the stability and activity of IRF7. Endogenous immunoprecipitation of Ro52-bound proteins revealed that IRF7 associates with Ro52, an effect which increases following TLR7 and TLR9 stimulation, suggesting that Ro52 interacts with IRF7 post-pathogen recognition. Furthermore, we show that Ro52 ubiquitinates IRF7 in a dose-dependent manner, resulting in a decrease in total IRF7 expression and a subsequent decrease in IFN-alpha production. IRF7 stability was increased in bone marrow-derived macrophages from Ro52-deficient mice stimulated with imiquimod or CpG-B, consistent with a role for Ro52 in the negative regulation of IRF7 signalling. Taken together, these results suggest that Ro52-mediated ubiquitination promotes the degradation of IRF7 following TLR7 and TLR9 stimulation. As Ro52 is known to be IFN-inducible, this system constitutes a negative-feedback loop that acts to protect the host from the prolonged activation of the immune response.-
dc.language.isoenen
dc.subjectIMMUNE SYSTEMen
dc.subjectGENETICSen
dc.subject.meshAnimals-
dc.subject.meshCell Line-
dc.subject.meshHela Cells-
dc.subject.meshHumans-
dc.subject.meshImmunoprecipitation-
dc.subject.meshInterferon Regulatory Factor-7-
dc.subject.meshInterferon-alpha-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshProtein Binding-
dc.subject.meshRibonucleoproteins-
dc.subject.meshToll-Like Receptor 7-
dc.subject.meshToll-Like Receptor 9-
dc.subject.meshToll-Like Receptors-
dc.subject.meshUbiquitination-
dc.titleSelf protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors.en
dc.typeArticleen
dc.contributor.departmentMolecular and Cellular Therapeutics and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.en
dc.identifier.journalPloS oneen

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