10 research outputs found
ULTRACYTOCHEMICAL STUDIES ON THE DIURNAL CHANGE OF THE ENZYMATIC ACTIVITY IN VARIOUS TISSUES OF THE RAT, WITH SPECIAL REFERENCE TO THE MITOCHONDRIAL OXIDOREDUCTASE ACTIVITY
ABCD3 and ABCD3-I Scores Are Superior to ABCD2 Score in the Prediction of Short- and Long-Term Risks of Stroke After Transient Ischemic Attack
Polymorphisms in the Lymphotoxin Alpha Gene and the Risk of Ischemic Stroke in the Japanese Population
Mst1 Promotes Cardiac Myocyte Apoptosis through Phosphorylation and Inhibition of Bcl-xL
Mst1 inhibits autophagy by promoting the interaction between beclin1 and Bcl-2
Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax