Cellular stress can cause the accumulation of aggregated proteins and organelles, and the process of autophagy sequesters these damaged cellular components into autophagosomes, which fuse with lysosomes for degradation. Autophagy requires Beclin1 and the class III phosphatidylinositide 3-kinase Vps34. Autophagy is increased in the heart under pathological conditions, such as myocardial ischemia, ischemia-reperfusion, and pressure overload. The Hippo pathway kinase Mst1 promotes dilated cardiomyopathy and the accumulation of protein aggresomes in the heart, leading Maejima et al. to investigate the link between Mst1, autophagy, and heart failure (see also Dhingra and Kirshenbaum). In hearts from mice with chronic myocardial infarction, aggresomes accumulated in cardiomyocytes at the border zone and remote areas of damage and colocalized with the cargo adaptor protein p62. Aggresome accumulation was reduced in mice that overexpressed a dominant-negative form of Mst1 in a cardiac-specific manner (Tg-DN-Mst1 mice) or in Mst1–/– mice. In mice expressing the autophagosome marker LC3 tagged with GFP, GFP-LC3–positive puncta accumulated in the border zone after myocardial infarction. This accumulation was reduced by concomitant overexpression of the dominant-negative form of Mst1 or genetic deficiency of Mst1. Cardiomyocytes from mice that overexpressed Mst1 in a cardiac-specific manner (Tg-Mst1 mice) showed increased protein aggregation, which was attenuated by expression of dominant-negative Mst1 or an shRNA directed against Mst1. In addition, cardiomyocytes cultured from Tg-Mst1 mice showed decreased autophagy. In isolated cardiomyocytes, overexpressed Mst1 interacted with Beclin1; furthermore, overexpression of Mst1 decreased the lipid kinase activity of Vps34. In Tg-DN-Mst1 and Mst1–/– hearts, the association of Beclin1 with Bcl-2 and Bcl-xL was increased; the Bcl proteins disrupt the interaction of Beclin1 with Vps34. The interaction of Beclin1 with the Bcl proteins requires the BH3 domain of Beclin1, and Mst1 phosphorylated Beclin1 at Thr108 in the BH3 domain, a phosphorylation event that triggered the homodimerization of Beclin1, which enhanced the interaction of Beclin1 with Bcl1. Mst1 activity, the phosphorylation of Thr108 in Beclin1, and p62 abundance were greater and autophagy was decreased in failing hearts from individuals with end-stage dilated cardiomyopathy compared with hearts from individuals with normal cardiac function. Thus, decreasing Mst1 activity to promote autophagy is a potential therapeutic strategy in heart failure.
Y. Maejima, S. Kyoi, P. Zhai, T. Liu, H. Li, A. Ivessa, S. Sciarretta, D. P. Del Re, D. K. Zablocki, C.-P. Hsu, D.-S. Lim, M. Isobe, J. Sadoshima, Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat. Med. 19, 1478–1488 (2013). [PubMed]
R. Dhingra, L. A. Kirshenbaum, Mst-1 switches between cardiac cell life and death. Nat. Med. 19, 1367–1368 (2013). [PubMed]