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GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover
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 bo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511875/ https://www.ncbi.nlm.nih.gov/pubmed/30854564 http://dx.doi.org/10.1093/nar/gkz163 |
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author | Garvin, Alexander J Khalaf, Ahmed H A Rettino, Alessandro Xicluna, Jerome Butler, Laura Morris, Joanna R Heery, David M Clarke, Nicole M |
author_facet | Garvin, Alexander J Khalaf, Ahmed H A Rettino, Alessandro Xicluna, Jerome Butler, Laura Morris, Joanna R Heery, David M Clarke, Nicole M |
author_sort | Garvin, Alexander J |
collection | PubMed |
description | 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 GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilized 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. |
format | Online Article Text |
id | pubmed-6511875 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-65118752019-05-20 GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover Garvin, Alexander J Khalaf, Ahmed H A Rettino, Alessandro Xicluna, Jerome Butler, Laura Morris, Joanna R Heery, David M Clarke, Nicole M Nucleic Acids Res Gene regulation, Chromatin and Epigenetics 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 GSK3β (Glycogen Synthase Kinase 3β) via phosphorylation of the T181 residue which generates a phosphodegron for the SCF (Skp-Cul-Fbox) ubiquitin E3-ligase receptor protein Fbxw7α (F-box/WD40 7). This regulated turnover is essential for IRF1 activity, as mutation of T181 results in an improperly stabilized 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. Oxford University Press 2019-05-21 2019-03-11 /pmc/articles/PMC6511875/ /pubmed/30854564 http://dx.doi.org/10.1093/nar/gkz163 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gene regulation, Chromatin and Epigenetics Garvin, Alexander J Khalaf, Ahmed H A Rettino, Alessandro Xicluna, Jerome Butler, Laura Morris, Joanna R Heery, David M Clarke, Nicole M GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title | GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title_full | GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title_fullStr | GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title_full_unstemmed | GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title_short | GSK3β-SCF(FBXW7α) mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover |
title_sort | gsk3β-scf(fbxw7α) mediated phosphorylation and ubiquitination of irf1 are required for its transcription-dependent turnover |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511875/ https://www.ncbi.nlm.nih.gov/pubmed/30854564 http://dx.doi.org/10.1093/nar/gkz163 |
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