Skip to main content

Research Repository

Advanced Search

GSK3?-SCFFBXW7? 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.


Alexander J. Garvin

Ahmed H.A. Khalaf

Alessandro Rettino

Jerome Xicluna

Laura Butler

Joanna R. Morris

Profile Image

Professor of Eucaryotic Gene Regulation

Nicole M. Clarke


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.


Garvin, A. J., Khalaf, A. H., Rettino, A., Xicluna, J., Butler, L., Morris, J. R., …Clarke, N. M. (2019). GSK3β-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover. Nucleic Acids Research, 47(9), 4476-4494.

Journal Article Type Article
Acceptance Date Mar 7, 2019
Online Publication Date Mar 11, 2019
Publication Date May 21, 2019
Deposit Date Mar 6, 2019
Publicly Available Date May 14, 2019
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 47
Issue 9
Article Number gkz163
Pages 4476-4494
Keywords Interferon Regulatory Factor-1; phosphodegron; GSK3; FBXW7
Public URL
Publisher URL


You might also like

Downloadable Citations