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

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

Journal article

Open access

Peer reviewed

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, …

Science (American Association for the Advancement of Science), Vol.362(6421), p.1375

12/21/2018

DOI: 10.1126/science.aan3303

PMCID: PMC6336677

PMID: 30409805

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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.

Calpain - metabolism

Humans

Myocardial Contraction - genetics

Cell Nucleus - metabolism

Adaptation, Physiological - genetics

Proteolysis

Muscle Proteins - metabolism

Ventricular Remodeling - genetics

Transcription, Genetic

Membrane Proteins - metabolism

Active Transport, Cell Nucleus

Membrane Proteins - genetics

Mice, Inbred C57BL

Gene Expression Regulation

Cardiomegaly - physiopathology

Mice, Transgenic

Excitation Contraction Coupling - genetics

Muscle Proteins - genetics

Myocytes, Cardiac - pathology

Animals

Membrane Proteins - chemistry

MEF2 Transcription Factors - metabolism

Myocytes, Cardiac - metabolism

Mice

Muscle Proteins - chemistry

Cardiomegaly - genetics

Details

Title: Subtitle: E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator
Creators: Ang Guo - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yihui Wang - Department of Emergency Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Biyi Chen - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yunhao Wang - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Jinxiang Yuan - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Liyang Zhang - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Duane Hall - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Jennifer Wu - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yun Shi - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Qi Zhu - Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu 226001, China
Cheng Chen - Department of Emergency Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
William H Thiel - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Xin Zhan - University of Iowa
Robert M Weiss - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Fenghuang Zhan - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Catherine A Musselman - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Miles Pufall - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Weizhong Zhu - Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu 226001, China
Kin Fai Au - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Jiang Hong - Department of Emergency Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
Mark E Anderson - Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Chad E Grueter - Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Long-Sheng Song - Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.362(6421), p.1375
DOI: 10.1126/science.aan3303
PMID: 30409805
PMCID: PMC6336677
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Grant note: S10 OD019941 / NIH HHS R01 HL125436 / NHLBI NIH HHS R35 HL140034 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS R01 HL130346 / NHLBI NIH HHS R01 HG008759 / NHGRI NIH HHS P30 DK054759 / NIDDK NIH HHS I01 BX002334 / BLRD VA P30 CA086862 / NCI NIH HHS
Language: English
Date published: 12/21/2018
Academic Unit: The University of Iowa Institute for Vision Research; Cardiovascular Medicine; Surgery; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094505702771

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