Mst1 Inhibits Autophagy by Promoting the Interaction Between Beclin1 and Bcl-2

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2013 Oct 22

PMID 24141421

Citations 283

Authors

Yasuhiro Maejima

Shiori Kyoi

Peiyong Zhai

Tong Liu

Hong Li

Andreas Ivessa

Sebastiano Sciarretta

Dominic P Del Re

Daniela K Zablocki

Chiao-Po Hsu

Dae-Sik Lim

Mitsuaki Isobe

Junichi Sadoshima

Affiliations

Soon will be listed here.

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.

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