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 Hong; Mark E. Anderson; Chad E. Grueter; Long Sheng Song

doi:10.1126/science.aan3303

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 E. Anderson, Chad E. Grueter, Long Sheng Song

School of Medicine

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion–dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found 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 nuclear 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 language	English (US)
Article number	aan3303
Journal	Science
Volume	362
Issue number	6421
DOIs	https://doi.org/10.1126/science.aan3303
State	Published - Dec 21 2018

ASJC Scopus subject areas

General

Access to Document

10.1126/science.aan3303

Cite this

Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., Zhan, X., Weiss, R. M., Zhan, F., Musselman, C. A., Pufall, M., Zhu, W., Au, K. F., ... Song, L. S. (2018). E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science, 362(6421), Article aan3303. https://doi.org/10.1126/science.aan3303

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, ME, Grueter, CE & Song, LS 2018, 'E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator', Science, vol. 362, no. 6421, aan3303. https://doi.org/10.1126/science.aan3303

@article{2c9acfa2eb9343af942e760b9d0ce61c,

title = "E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator",

abstract = "Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion–dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found 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 nuclear 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.",

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

year = "2018",

month = dec,

day = "21",

doi = "10.1126/science.aan3303",

language = "English (US)",

volume = "362",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6421",

}

TY - JOUR

T1 - E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator

AU - Guo, Ang

AU - Wang, Yihui

AU - Chen, Biyi

AU - Wang, Yunhao

AU - Yuan, Jinxiang

AU - Zhang, Liyang

AU - Hall, Duane

AU - Wu, Jennifer

AU - Shi, Yun

AU - Zhu, Qi

AU - Chen, Cheng

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 E.

AU - Grueter, Chad E.

AU - Song, Long Sheng

PY - 2018/12/21

Y1 - 2018/12/21

N2 - Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion–dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found 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 nuclear 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.

AB - Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion–dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found 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 nuclear 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.

UR - http://www.scopus.com/inward/record.url?scp=85056567995&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056567995&partnerID=8YFLogxK

U2 - 10.1126/science.aan3303

DO - 10.1126/science.aan3303

M3 - Article

C2 - 30409805

AN - SCOPUS:85056567995

SN - 0036-8075

VL - 362

JO - Science

JF - Science

IS - 6421

M1 - aan3303

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this