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

Author

Listed:
  • Yasuhiro Maejima

    (Rutgers New Jersey Medical School
    Tokyo Medical and Dental University)

  • Jihoon Nah

    (Rutgers New Jersey Medical School
    Chungbuk National University)

  • 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)

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.

Suggested Citation

  • Yasuhiro Maejima & Jihoon Nah & Zahra Aryan & Peiyong Zhai & Eun-Ah Sung & Tong Liu & Koichiro Takayama & Siavash Moghadami & Tetsuo Sasano & Hong Li & Junichi Sadoshima, 2024. "Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50393-y
    DOI: 10.1038/s41467-024-50393-y
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