GSK3?-SCFFBXW7? mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover
| Autor: | Garvin, Alexander J., Khalaf, Ahmed H.A., Rettino, Alessandro, Xicluna, Jerome, Butler, Laura, Morris, Joanna R., Heery, David M., Clarke, Nicole M. |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: | |
| ISSN: | 0305-1048 1362-4962 |
| Popis: | IRF1 (Interferon Regulatory Factor-1) is the prototype of the IRF family of DNA binding transcription factors. IRF1 protein expression is regulated by transient up-regulation in response to external stimuli followed by rapid degradation via the ubiquitin-proteasome system. Here we report that DNA bound IRF1 turnover is promoted by GSK3? (Glycogen Synthase Kinase 3?) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7? (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilised protein that accumulates at target promoters but fails to induce RNA-Pol-II elongation and subsequent transcription of target genes. Consequently, the anti-proliferative activity of IRF1 is lost in cell lines expressing T181A mutant. Further, cell lines with dysfunctional Fbxw7 are less sensitive to IRF1 overexpression, suggesting an important co-activator function for this ligase complex. As T181 phosphorylation requires both DNA binding and RNA-Pol-II elongation, we propose that this event acts to clear " spent " molecules of IRF1 from transcriptionally engaged target promoters. |
| Databáze: | OpenAIRE |
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