title: Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2.
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.
authors.affiliation: 1] 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.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Shiori
authors.initials: S
authors.lastname: Kyoi
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Andreas
authors.initials: A
authors.lastname: Ivessa
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Del Re
authors.forename: Daniela K
authors.initials: DK
authors.lastname: Zablocki
authors.forename: Chiao-Po
authors.initials: CP
authors.lastname: Hsu
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D058546:Class III Phosphatidylinositol 3-Kinases