Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39060225.
- Also identified by DOI 10.1038/s41467-024-50393-y and PMC identifier 11282193.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The molecular mechanisms by which FoxO transcription factors mediate diametrically opposite cellular responses, namely death and survival, remain unknown. Here we show that Mst1 phosphorylates FoxO1 Ser209/Ser215/Ser218/Thr228/Ser232/Ser243, thereby inhibiting FoxO1-mediated transcription of proapoptotic genes. On the other hand, Mst1 increases FoxO1-C/EBP-β interaction and activates C/EBP-β by phosphorylating it at Thr299, thereby promoting transcription of prosurvival genes. Myocardial ischemia/reperfusion injury is larger in cardiac-specific FoxO1 knockout mice than in control mice. However, the concurrent presence of a C/EBP-β T299E phospho-mimetic mutation reduces infarct size in cardiac-specific FoxO1 knockout mice. The C/EBP-β phospho-mimetic mutant exhibits greater binding to the promoter of prosurvival genes than wild type C/EBP-β. In conclusion, phosphorylation of FoxO1 by Mst1 inhibits binding of FoxO1 to pro-apoptotic gene promoters but enhances its binding to C/EBP-β, phosphorylation of C/EBP-β, and transcription of prosurvival genes, which stimulate protective mechanisms in the heart.
Medical subject headings
- CCAAT-Enhancer-Binding Protein-beta
- Forkhead Box Protein O1
- Myocardial Reperfusion Injury
- Myocytes, Cardiac