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E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator
Ang Guo1, Yihui Wang1,2, Biyi Chen1
1Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Science (New York, N.Y.)
|November 10, 2018
Summary
Junctophilin-2 (JP2) cleavage during cardiac stress releases a nuclear fragment (JP2NT). This fragment reprograms gene expression, offering a protective mechanism against heart failure progression.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Heart Failure Pathophysiology
Background:
- Junctophilin-2 (JP2) is crucial for cardiac excitation-contraction (E-C) coupling.
- Cardiac stress leads to JP2 cleavage by calpain, impairing E-C coupling and promoting heart failure.
Purpose of the Study:
- To investigate the role of JP2 cleavage products in cardiomyocytes.
- To determine the function of the N-terminal fragment (JP2NT) of JP2 after cardiac stress.
Main Methods:
- Utilized transgenic mouse models with altered JP2NT expression.
- Analyzed transcriptional profiles and cardiac remodeling in response to stress.
- Investigated nuclear translocation and DNA binding of JP2NT.
Main Results:
- Stress-induced JP2 proteolysis releases JP2NT, which enters the nucleus.
- Nuclear JP2NT binds DNA and modulates gene expression in cardiomyocytes.
- Overexpression of JP2NT attenuates pathological remodeling, while its loss accelerates heart failure.
Conclusions:
- JP2NT acts as a transcription factor in response to cardiac stress.
- Nuclear JP2NT mediates a protective transcriptional reprogramming in failing cardiomyocytes.
- This mechanism represents a self-protective response to mechanical stress in the heart.
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