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.
Mesh Terms:
Adult, Amino Acid Sequence, Animals, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Cardiomyopathy, Dilated, Class III Phosphatidylinositol 3-Kinases, Female, Hepatocyte Growth Factor, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Models, Molecular, Molecular Sequence Data, Myocardial Infarction, Myocytes, Cardiac, Phosphorylation, Protein Multimerization, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Rats, Young Adult, bcl-2-Associated X Protein
Adult, Amino Acid Sequence, Animals, Apoptosis, Apoptosis Regulatory Proteins, Autophagy, Beclin-1, Cardiomyopathy, Dilated, Class III Phosphatidylinositol 3-Kinases, Female, Hepatocyte Growth Factor, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Middle Aged, Models, Molecular, Molecular Sequence Data, Myocardial Infarction, Myocytes, Cardiac, Phosphorylation, Protein Multimerization, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Rats, Young Adult, bcl-2-Associated X Protein
Nat. Med.
Date: Nov. 01, 2013
PubMed ID: 24141421
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