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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article numberaan3303
JournalScience
Volume362
Issue number6421
DOIs
StatePublished - Dec 21 2018

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    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), [aan3303]. https://doi.org/10.1126/science.aan3303