RRC ID 28125
Author Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, Sciarretta S, Del Re DP, Zablocki DK, Hsu CP, Lim DS, Isobe M, Sadoshima J.
Title Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2.
Journal Nat Med
Abstract 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.
Volume 19(11)
Pages 1478-88
Published 2013-11-1
DOI 10.1038/nm.3322
PII nm.3322
PMID 24141421
PMC PMC3823824
MeSH Adult Amino Acid Sequence Animals Apoptosis / physiology Apoptosis Regulatory Proteins / chemistry Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism* Autophagy / physiology* Beclin-1 Cardiomyopathy, Dilated / metabolism Cardiomyopathy, Dilated / pathology Class III Phosphatidylinositol 3-Kinases / antagonists & inhibitors Class III Phosphatidylinositol 3-Kinases / metabolism Female Hepatocyte Growth Factor / deficiency Hepatocyte Growth Factor / genetics Hepatocyte Growth Factor / metabolism* Humans Male Membrane Proteins / chemistry Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Middle Aged Models, Molecular Molecular Sequence Data Myocardial Infarction / metabolism Myocardial Infarction / pathology Myocytes, Cardiac / cytology Myocytes, Cardiac / metabolism Phosphorylation Protein Multimerization Proto-Oncogene Proteins / deficiency Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Proto-Oncogene Proteins c-bcl-2 / metabolism* Rats Young Adult bcl-2-Associated X Protein / metabolism
IF 30.641
Times Cited 254
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
Mice GFP-LC3#53(RBRC00806)