Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes

Yasuhiro Maejima, Jihoon Nah, Zahra Aryan, Peiyong Zhai, Eun-Ah Sung, Tong Liu, Koichiro Takayama, Siavash Moghadami, Tetsuo Sasano, Hong Li and Junichi Sadoshima ()
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Yasuhiro Maejima: Rutgers New Jersey Medical School
Jihoon Nah: Rutgers New Jersey Medical School
Zahra Aryan: Rutgers New Jersey Medical School
Peiyong Zhai: Rutgers New Jersey Medical School
Eun-Ah Sung: Rutgers New Jersey Medical School
Tong Liu: Rutgers New Jersey Medical School
Koichiro Takayama: Rutgers New Jersey Medical School
Siavash Moghadami: Stanford University School of Medicine
Tetsuo Sasano: Tokyo Medical and Dental University
Hong Li: Rutgers New Jersey Medical School
Junichi Sadoshima: Rutgers New Jersey Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50393-y

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