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Spliced X-Box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR.

BACKGROUND
The unfolded protein response (UPR) plays versatile roles in physiology and pathophysiology. Its connection to cell growth however remains elusive. Here, we sought to define the role of UPR in regulation of cardiomyocyte growth in the heart.


METHODS
We used both gain- and loss-of-function approaches to genetically manipulate spliced X-box binding protein 1 (XBP1s), the most conserved signaling branch of the UPR, in the heart. In addition, primary cardiomyocyte culture was employed to address the role of XBP1s in cell growth in a cell-autonomous manner.


RESULTS
We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Further, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin (mTOR) signaling, which is mediated via FK506-binding protein 11 (FKBP11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mTOR activation and adaptive cell growth.


CONCLUSIONS
Our results reveal a critical role of the XBP1s-FKBP11-mTOR axis in coupling the UPR and cardiac cell growth regulation.