Translational control of Ybx1 expression regulates cardiac function in response to pressure overload in vivo
Eshita Varma1,2, Jana Burghaus1,2, Thomas Schwarzl3
1Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Abstract:
RNA-protein interactions are central to cardiac function, but how activity of individual RNA-binding protein is regulated through signaling cascades in cardiomyocytes during heart failure development is largely unknown. The mechanistic target of rapamycin kinase is a central signaling hub that controls mRNA translation in cardiomyocytes; however, a direct link between mTOR signaling and RNA-binding proteins in the heart has not been established. Integrative transcriptome and translatome analysis revealed mTOR dependent translational upregulation of the RNA binding protein Ybx1 during early pathological remodeling independent of mRNA levels. Ybx1 is necessary for pathological cardiomyocyte growth by regulating protein synthesis. To identify the molecular mechanisms how Ybx1 regulates cellular growth and protein synthesis, we identified mRNAs bound to Ybx1. We discovered that eucaryotic elongation factor 2 (Eef2) mRNA is bound to Ybx1, and its translation is upregulated during cardiac hypertrophy dependent on Ybx1 expression. Eef2 itself is sufficient to drive pathological growth by increasing global protein translation. Finally, Ybx1 depletion in vivo preserved heart function during pathological cardiac hypertrophy. Thus, activation of mTORC1 links pathological signaling cascades to altered gene expression regulation by activation of Ybx1 which in turn promotes translation through increased expression of Eef2.
Insights
Heart failure involves RNA-binding proteins. Mechanistic target of rapamycin kinase (mTORC1) signaling activates Y-box binding protein 1 (Ybx1), driving pathological growth by increasing protein synthesis via Eef2.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- RNA Biology
Background:
- RNA-protein interactions are crucial for heart function.
- Regulation of RNA-binding proteins by signaling in heart failure is poorly understood.
- Mechanistic target of rapamycin kinase (mTOR) regulates translation in cardiomyocytes.
Purpose of the Study:
- Investigate the link between mTOR signaling and RNA-binding proteins in heart failure.
- Determine the role of Y-box binding protein 1 (Ybx1) in pathological cardiac remodeling.
- Elucidate the molecular mechanisms by which Ybx1 regulates cardiomyocyte growth and protein synthesis.
Main Methods:
- Integrative transcriptome and translatome analysis.
- Identification of messenger RNAs (mRNAs) bound by Ybx1.
- In vivo Ybx1 depletion studies in a cardiac hypertrophy model.
Main Results:
- mTORC1 signaling upregulates Ybx1 translation, independent of mRNA levels, during early pathological remodeling.
- Ybx1 is essential for pathological cardiomyocyte growth by regulating protein synthesis.
- Ybx1 binds and upregulates the translation of eukaryotic elongation factor 2 (Eef2) mRNA, promoting global protein translation and pathological growth.
- Ybx1 depletion preserves cardiac function during pathological cardiac hypertrophy.
Conclusions:
- mTORC1 activation links pathological signaling to altered gene expression via Ybx1.
- Ybx1 promotes pathological cardiac hypertrophy by increasing Eef2 translation and global protein synthesis.
- Targeting the mTORC1-Ybx1-Eef2 axis may offer therapeutic strategies for heart failure.
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