Type

Journal Article

Authors

Caroline A Jefferies
Katherine A Fitzgerald
Eamon P Breen
Nadia Ben Larbi
Joan Ní Gabhann
Rowan Higgs

Subjects

Biochemistry

Topics
ss a antigen tlr4 protein human biosynthesis dead box rna helicases toll like receptor 4 toll like receptor 3 cell line ddx58 protein human irf3 protein human polyubiquitin interferon regulatory factor 3 humans promoter regions genetic ribonucleoproteins immunology protein binding tlr3 protein human genetics signal transduction interferon beta ubiquitin protein ligases metabolism

The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. (2008)

Abstract Induction of type I IFNs is a fundamental cellular response to both viral and bacterial infection. The role of the transcription factor IRF3 is well established in driving this process. However, equally as important are cellular mechanisms for turning off type I IFN production to limit this response. In this respect, IRF3 has previously been shown to be targeted for ubiquitin-mediated degradation postviral detection to turn off the IFN-beta response. In this study, we provide evidence that the E3 ligase Ro52 (TRIM21) targets IRF3 for degradation post-pathogen recognition receptor activation. We demonstrate that Ro52 interacts with IRF3 via its C-terminal SPRY domain, resulting in the polyubiquitination and proteasomal degradation of the transcription factor. Ro52-mediated IRF3 degradation significantly inhibits IFN-beta promoter activity, an effect that is reversed in the presence of the proteasomal inhibitor MG132. Specific targeting of Ro52 using short hairpin RNA rescues IRF3 degradation following polyI:C-stimulation of HEK293T cells, with a subsequent increase in IFN-beta production. Additionally, shRNA targeting of murine Ro52 enhances the production of the IRF3-dependent chemokine RANTES following Sendai virus infection of murine fibroblasts. Collectively, this demonstrates a novel role for Ro52 in turning off and thus limiting IRF3-dependent type I IFN production by targeting the transcription factor for polyubiquitination and subsequent proteasomal degradation.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Caroline A Jefferies, Katherine A Fitzgerald, Eamon P Breen, Nadia Ben Larbi, Joan Ní Gabhann, Rowan Higgs

Experts in our system

1
Caroline A Jefferies
Royal College of Surgeons in Ireland
Total Publications: 50
 
2
Joan Ní Gabhann
Royal College of Surgeons in Ireland
Total Publications: 23