The transcription factor IRF1 plays important roles in interferon-mediated cellular responses

The transcription factor IRF1 plays important roles in interferon-mediated cellular responses.

In addition to its role in cell responses to viral and bacterial infections, IRF1 also regulates response to DNA damage, apoptosis and is required to suppress tumour growth.

This study reveals new molecular insights into the how IRF1 itself is regulated by the proteins GSK3b and FBXW7a.

Glycogen synthase kinase (GSK3b) is a proline-directed serine threonine kinase that phosphorylates IRF1 at a specific threonine residue (T181).

This induces ubiquitinylation of IRF1 by FBXW7a E3 ligase complexes  and promotes degradation by proteasomes

We found that IRF1 T181 mutants fail to be removed from the TRAIL promoter and other IRF1 target gene promoters. As a consequence, this hampers RNA PolII transcriptional elongation on these genes.

Thus remarkably, IRF1 ‘turnover’ happens in situ on gene promoters and is essential for transcription by IRF1.

The paper was published in the journal Nucleic Acids Research - please follow the link below to view the publication: 

GSK3β-SCFFBXW7α mediated phosphorylation and ubiquitination of IRF1 are required for its transcription-dependent turnover.

Garvin AJ, Khalaf AHA, Rettino A, Xicluna J, Butler L, Morris JR, Heery DM, Clarke NM.

Nucleic Acids Res. 2019 Mar 11. pii: gkz163. doi: 10.1093/nar/gkz163. [Epub ahead of print]

PMID: 30854564