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 Wang

Research output: Contribution to journalArticle

1 Citation (Scopus)

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, 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 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

Fingerprint

Unfolded Protein Response
Growth
Tacrolimus Binding Proteins
Sirolimus
Cardiac Myocytes
Heart Failure
X-Box Binding Protein 1
Rodentia
Pressure

Keywords

  • FKBP11 protein, human
  • FKBP11 protein, mouse
  • heart failure
  • hypertrophy
  • mTOR protein, mouse
  • unfolded protein response
  • X-box binding protein 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR. / Wang, Xiaoding; Deng, Yingfeng; Zhang, Guangyu; Li, Chao; Ding, Guanqiao; May, Herman I.; Tran, Diem H.; Luo, Xiang; Jiang, Ding Sheng; Li, Dan L.; Wei, Xiang; Xu, Lin; Ferdous, Anwarul; Gillette, Thomas G.; Scherer, Philipp E; Jiang, Xuejun; Wang, Zhao.

In: Circulation, Vol. 140, No. 7, 13.08.2019, p. 566-579.

Research output: Contribution to journalArticle

Wang, X, Deng, Y, Zhang, G, Li, C, Ding, G, May, HI, Tran, DH, Luo, X, Jiang, DS, Li, DL, Wei, X, Xu, L, Ferdous, A, Gillette, TG, Scherer, PE, Jiang, X & Wang, Z 2019, 'Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR', Circulation, vol. 140, no. 7, pp. 566-579. https://doi.org/10.1161/CIRCULATIONAHA.118.038924
Wang, Xiaoding ; Deng, Yingfeng ; Zhang, Guangyu ; Li, Chao ; Ding, Guanqiao ; May, Herman I. ; Tran, Diem H. ; Luo, Xiang ; Jiang, Ding Sheng ; Li, Dan L. ; Wei, Xiang ; Xu, Lin ; Ferdous, Anwarul ; Gillette, Thomas G. ; Scherer, Philipp E ; Jiang, Xuejun ; Wang, Zhao. / Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR. In: Circulation. 2019 ; Vol. 140, No. 7. pp. 566-579.
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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, 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 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.",
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T1 - Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR

AU - Wang, Xiaoding

AU - Deng, Yingfeng

AU - Zhang, Guangyu

AU - Li, Chao

AU - Ding, Guanqiao

AU - May, Herman I.

AU - Tran, Diem H.

AU - Luo, Xiang

AU - Jiang, Ding Sheng

AU - Li, Dan L.

AU - Wei, Xiang

AU - Xu, Lin

AU - Ferdous, Anwarul

AU - Gillette, Thomas G.

AU - Scherer, Philipp E

AU - Jiang, Xuejun

AU - Wang, Zhao

PY - 2019/8/13

Y1 - 2019/8/13

N2 - 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, 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 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.

AB - 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, 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 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.

KW - FKBP11 protein, human

KW - FKBP11 protein, mouse

KW - heart failure

KW - hypertrophy

KW - mTOR protein, mouse

KW - unfolded protein response

KW - X-box binding protein 1

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