Spliced X-box binding protein 1 stimulates adaptive growth through activation of mTOR

Xiaoding Wang, Yingfeng Deng, Guangyu Zhang, Chao Li, Guanqiao Ding, Herman I. May, Diem H. Tran, Xiang Luo, Ding Sheng Jiang, Dan L. Li, Xiang Wei, Lin Xu, Anwarul Ferdous, Thomas G Gillette, Philipp E. Scherer, Xuejun Jiang, Zhao V. Wang

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

BACKGROUND: The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. METHODS: We used both gain-and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used 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. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiacrestricted 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 signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. CONCLUSIONS: Our results reveal a critical role of the XBP1s-FKBP11-mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.

Original languageEnglish (US)
Pages (from-to)566-579
Number of pages14
JournalCirculation
Volume140
Issue number7
DOIs
StatePublished - Aug 13 2019

Keywords

  • FKBP11 protein, human
  • FKBP11 protein, mouse
  • Heart failure
  • Hypertrophy
  • X-box binding protein 1
  • mTOR protein, mouse
  • unfolded protein response

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Wang, X., Deng, Y., Zhang, G., Li, C., Ding, G., May, H. I., Tran, D. H., Luo, X., Jiang, D. S., Li, D. L., Wei, X., Xu, L., Ferdous, A., Gillette, T. G., Scherer, P. E., Jiang, X., & Wang, Z. V. (2019). Spliced X-box binding protein 1 stimulates adaptive growth through activation of mTOR. Circulation, 140(7), 566-579. https://doi.org/10.1161/CIRCULATIONAHA.118.038924