MST1 negatively regulates autophagy in cardiomyocytes through phosphorylation of Beclin-1.

  • Major finding: MST1 negatively regulates autophagy in cardiomyocytes through phosphorylation of Beclin-1.

  • Mechanism: Beclin-1 phosphorylation promotes BCL-2 binding to Beclin-1, which allows BAX activation.

  • Impact: MST1 may link the Hippo pathway to regulation of autophagy and apoptosis in other cell types.

The Hippo signaling pathway controls organ size through the regulation of cell proliferation and apoptosis and is frequently deregulated in cancer. Macrophage stimulating 1 (MST1) is a Hippo pathway kinase and putative tumor suppressor with proapoptotic activity. Preliminary studies indicated that stress-induced upregulation of MST1 was not only associated with cardiomyocyte apoptosis but also an accumulation of damaged proteins and organelles consistent with the decrease in autophagy that accompanies heart failure. Maejima and colleagues found that deletion of Mst1 or cardiac-specific expression of dominant-negative Mst1 in mice led to a reduction in damaged protein and organelle aggregates that was dependent on Beclin-1, a regulator of autophagosome formation, providing further evidence that MST1 is a negative regulator of autophagy. Indeed, MST1 overexpression inhibited autophagy in cardiomyocytes in a cell-autonomous manner by directly binding Beclin-1 and reducing formation and activity of the Beclin-1–VPS34 complex. Upstream regulators, but not downstream effectors, of MST1 also inhibited autophagy, suggesting that Hippo signaling negatively regulates autophagy through MST1. Mechanistically, MST1 phosphorylated Beclin-1 on threonine 108, which promoted an interaction with the antiapoptotic proteins BCL-2 or BCL-XL and enhanced Beclin-1 homodimerization. The MST1-induced sequestration of BCL-2 and BCL-XL by Beclin-1 also stimulated BAX-dependent apoptosis, as the amounts of BCL-2–bound BAX decreased and free, active BAX increased. Although these findings need to be verified in other tissues as well as in the context of cancer cells, they raise the possibility that coordinate regulation of autophagy and apoptosis by MST1 may contribute to tumor suppression by the Hippo pathway.

Maejima Y, Kyoi S, Zhai P, Liu T, Li H, Ivessa A, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 2013 Oct 20 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013