E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator

Ang Guo, Yihui Wang, Biyi Chen, Yunhao Wang, Jinxiang Yuan, Liyang Zhang, Duane Hall, Jennifer Wu, Yun Shi, Qi Zhu, Cheng Chen, William H. Thiel, Xin Zhan, Robert M. Weiss, Fenghuang Zhan, Catherine A. Musselman, Miles Pufall, Weizhong Zhu, Kin Fai Au, Jiang HongMark Anderson, Chad E. Grueter, Long Sheng Song

Research output: Contribution to journalArticle

Abstract

Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. Following cardiac stress, JP2 is cleaved by Ca2+-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. Here we demonstrate that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.

Original languageEnglish (US)
JournalScience
DOIs
StateAccepted/In press - Jan 1 2018

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Excitation Contraction Coupling
Cardiac Myocytes
Heart Failure
Proteins
Calpain
Hypertrophy
Proteolysis
Peptide Hydrolases
DNA
Genes
junctophilin

ASJC Scopus subject areas

  • General

Cite this

Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., ... Song, L. S. (Accepted/In press). E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science. https://doi.org/10.1126/science.aan3303

E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. / Guo, Ang; Wang, Yihui; Chen, Biyi; Wang, Yunhao; Yuan, Jinxiang; Zhang, Liyang; Hall, Duane; Wu, Jennifer; Shi, Yun; Zhu, Qi; Chen, Cheng; Thiel, William H.; Zhan, Xin; Weiss, Robert M.; Zhan, Fenghuang; Musselman, Catherine A.; Pufall, Miles; Zhu, Weizhong; Au, Kin Fai; Hong, Jiang; Anderson, Mark; Grueter, Chad E.; Song, Long Sheng.

In: Science, 01.01.2018.

Research output: Contribution to journalArticle

Guo, A, Wang, Y, Chen, B, Wang, Y, Yuan, J, Zhang, L, Hall, D, Wu, J, Shi, Y, Zhu, Q, Chen, C, Thiel, WH, Zhan, X, Weiss, RM, Zhan, F, Musselman, CA, Pufall, M, Zhu, W, Au, KF, Hong, J, Anderson, M, Grueter, CE & Song, LS 2018, 'E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator', Science. https://doi.org/10.1126/science.aan3303
Guo, Ang ; Wang, Yihui ; Chen, Biyi ; Wang, Yunhao ; Yuan, Jinxiang ; Zhang, Liyang ; Hall, Duane ; Wu, Jennifer ; Shi, Yun ; Zhu, Qi ; Chen, Cheng ; Thiel, William H. ; Zhan, Xin ; Weiss, Robert M. ; Zhan, Fenghuang ; Musselman, Catherine A. ; Pufall, Miles ; Zhu, Weizhong ; Au, Kin Fai ; Hong, Jiang ; Anderson, Mark ; Grueter, Chad E. ; Song, Long Sheng. / E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. In: Science. 2018.
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AU - Zhang, Liyang

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AU - Thiel, William H.

AU - Zhan, Xin

AU - Weiss, Robert M.

AU - Zhan, Fenghuang

AU - Musselman, Catherine A.

AU - Pufall, Miles

AU - Zhu, Weizhong

AU - Au, Kin Fai

AU - Hong, Jiang

AU - Anderson, Mark

AU - Grueter, Chad E.

AU - Song, Long Sheng

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