Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2.
Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2.
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在这里，我们表明，Mst 1，促凋亡激酶，损害蛋白质的质量控制机制，在心脏通过抑制自噬。应激诱导的心肌细胞Mst 1的激活促进了p62的积累和侵袭体的形成，伴随着自噬体的消失。Mst 1磷酸化Beclin 1 BH 3结构域中的Thr 108残基，增强Beclin 1与Bcl-2和/或Bcl-xL之间的相互作用，稳定Beclin 1同源二聚体，抑制Atg 14 L-Beclin 1-Vps 34复合物的磷脂酰肌醇3-激酶活性，并抑制自噬。此外，Mst 1诱导的Beclin 1对Bcl-2和Bcl-xL的隔离使Bax变得活跃，从而刺激细胞凋亡。Mst 1通过抑制自噬促进心肌梗死小鼠的心功能障碍，与Thr 108-磷酸化Beclin 1水平升高相关。此外，人类扩张型心肌病与Thr 108-磷酸化Beclin 1水平增加和自噬抑制迹象相关。这些结果表明，Mst 1协调调节自噬和细胞凋亡的磷酸化Beclin 1，从而调节Bcl-2蛋白，Beclin 1和Bax之间的三方相互作用。
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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