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Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2

Yasuhiro Maejima1, Shiori Kyoi, Peiyong Zhai

  • 11] Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, USA. [2] Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Nature Medicine
|October 22, 2013
PubMed

Insights

The proapoptotic kinase Mst1 inhibits autophagy, a key protein quality control process in the heart. This leads to cardiac dysfunction and dilated cardiomyopathy by disrupting the Beclin1-Bcl-2-Bax interaction.

Area of Science:

  • Cardiovascular Biology
  • Cellular Mechanisms
  • Molecular Cardiology

Background:

  • Protein quality control is crucial for cardiac function.
  • Autophagy, a cellular degradation process, is vital for maintaining heart health.
  • Dysregulation of autophagy is implicated in cardiac diseases.

Purpose of the Study:

  • To investigate the role of Mst1 kinase in cardiac protein quality control.
  • To elucidate the mechanism by which Mst1 affects autophagy in cardiomyocytes.
  • To determine the link between Mst1, autophagy, and cardiac dysfunction.

Main Methods:

  • Studied Mst1 activation in cardiomyocytes under stress.
  • Analyzed p62, aggresome, and autophagosome levels.
  • Investigated Mst1 phosphorylation of Beclin1 at Thr108.
  • Assessed interactions between Beclin1, Bcl-2, Bcl-xL, and Bax.
  • Examined cardiac function in Mst1-manipulated mice and human dilated cardiomyopathy patients.

Main Results:

  • Mst1 activation inhibited autophagy and promoted aggresome formation.
  • Mst1 phosphorylated Beclin1 at Thr108, enhancing Beclin1-Bcl-2/Bcl-xL interaction and inhibiting autophagy.
  • Mst1-induced Beclin1 sequestration of Bcl-2/Bcl-xL activated Bax, promoting apoptosis.
  • Mst1 inhibition of autophagy correlated with cardiac dysfunction in myocardial infarction mice.
  • Increased Thr108-phosphorylated Beclin1 and suppressed autophagy were observed in human dilated cardiomyopathy.

Conclusions:

  • Mst1 impairs cardiac protein quality control by inhibiting autophagy.
  • Mst1 phosphorylation of Beclin1 at Thr108 is a key mechanism linking Mst1 to autophagy and apoptosis.
  • Mst1 represents a potential therapeutic target for cardiac diseases associated with autophagic dysfunction.

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