title: TRIpartite motif 21 (TRIM21) differentially regulates the stability of interferon regulatory factor 5 (IRF5) isoforms.
abstract: IRF5 is a member of the Interferon Regulatory Factor (IRF) family of transcription factors activated downstream of the Toll-Like receptors (TLRs). Polymorphisms in IRF5 have been shown to be associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) and other autoimmune conditions, suggesting a central role for IRF5 in the regulation of the immune response. Four different IRF5 isoforms originate due to alternative splicing and to the presence or absence of a 30 nucleotide insertion in IRF5 exon 6. Since the polymorphic region disturbs a PEST domain, a region associated with protein degradation, we hypothesized that the isoforms bearing the insertion might have increased stability, thus explaining the association of individual IRF5 isoforms with SLE. As the E3 ubiquitin ligase TRIpartite Motif 21 (TRIM21) has been shown to regulate the stability and hence activity of members of the IRF family, we investigated whether IRF5 is subjected to regulation by TRIM21 and whether dysregulation of this mechanism could explain the association of IRF5 with SLE. Our results show that IRF5 is degraded following TLR7 activation and that TRIM21 is involved in this process. Comparison of the individual IRF5 variants demonstrates that isoforms generated by alternative splicing are resistant to TRIM21-mediated degradation following TLR7 stimulation, thus providing a functional link between isoforms expression and stability/activity which contributes to explain the association of IRF5 with SLE.
authors.affiliation: Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lazzari
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, Newark, New Jersey, United States of America, Rutgers Biomedical and Health Sciences, New Jersey Medical School- Cancer Center, Newark, New Jersey, United States of America.
authors.forename: Justyna
authors.initials: J
authors.lastname: Korczeniewska
authors.affiliation: Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Joan
authors.initials: J
authors.lastname: Ní Gabhann
authors.affiliation: Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, Newark, New Jersey, United States of America, Rutgers Biomedical and Health Sciences, New Jersey Medical School- Cancer Center, Newark, New Jersey, United States of America.
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Barnes
authors.affiliation: Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Jefferies
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D060888:Real-Time Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D000099207:SS-A Antigen
chemical_list: D050835:Interferon Regulatory Factors; D020033:Protein Isoforms; D012261:Ribonucleoproteins; D051199:Toll-Like Receptor 7; D000099207:SS-A Antigen; C431713:IRF5 protein, human; C495348:TLR7 protein, human
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