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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Acknowledgements
We thank C. Brady for critical reading of the manuscript and Y. Ikeda, Y. Matsuda and N. Tamura for their excellent technical assistance. We also thank N. Mizushima (University of Tokyo) for Tg-GFP-LC3 mice, T. Yoshimori (Osaka University) for mRFP-GFP-LC3 plasmid, C. Kojima (Nara Institute of Science and Technology) for pCold-GST plasmid, M. Komatsu (Tokyo Metropolitan Institute of Medical Science) for Atg7flox/flox mice, R. Kitsis (Albert Einstein College of Medicine) for Bax−/−; Bak1−/− MEFs, and B. Levine (University of Texas Southwestern) for Becn1+/− mice. This work was supported in part by US Public Health Service grants HL59139, HL67724, HL69020, HL91469, HL102738 and AG27211, the Foundation of Leducq Transatlantic Network of Excellence (J.S.), American Heart Association Scientist Development Grant 12SDG12070262 and the Banyu Fellowship Program sponsored by Banyu Life Science Foundation International (Y.M.).
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Y.M. designed and performed experiments, analyzed data and wrote the manuscript. S.K. designed and performed experiments and analyzed data. P.Z. performed animal surgery. T.L. and H.L. performed experiments and analyzed data regarding proteomic analyses. A.I., S.S., D.P.D.R., and C.-P.H. performed experiments and analyzed data. D.K.Z. wrote the manuscript. D.-S.L. provided the animals and cells and supervised the project. M.I. supervised the project. J.S. designed the studies, analyzed the data and wrote the manuscript.
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Maejima, Y., Kyoi, S., Zhai, P. et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 19, 1478–1488 (2013). https://doi.org/10.1038/nm.3322
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DOI: https://doi.org/10.1038/nm.3322
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