Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors.
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.
Higgs
Rowan
R
Molecular and Cellular Therapeutics and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
Lazzari
Elisa
E
Wynne
Claire
C
Ní Gabhann
Joan
J
Espinosa
Alexander
A
Wahren-Herlenius
Marie
M
Jefferies
Caroline A
CA
D000818:Animals; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099207:SS-A Antigen
D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D012261:Ribonucleoproteins; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D000099207:SS-A Antigen; C494234:IRF7 protein, human