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.

• Authors: 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
• Journal: Science (New York, N.Y.) (Science) Vol. 362 Issue 6421 (12 21 2018) ISSN: 1095-9203 [Electronic] United States
• PMID: 30409805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• MEF2 Transcription Factors
• Membrane Proteins
• Muscle Proteins
• junctophilin-2 protein, mouse
• Calpain

Topics

• Active Transport, Cell Nucleus
• Adaptation, Physiological (genetics)
• Animals
• Calpain (metabolism)
• Cardiomegaly (genetics, physiopathology)
• Cell Nucleus (metabolism)
• Excitation Contraction Coupling (genetics)
• Gene Expression Regulation
• Humans
• MEF2 Transcription Factors (metabolism)
• Membrane Proteins (chemistry, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscle Proteins (chemistry, genetics, metabolism)
• Myocardial Contraction (genetics)
• Myocytes, Cardiac (metabolism, pathology)
• Proteolysis
• Transcription, Genetic
• Ventricular Remodeling (genetics)