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.

RNA-蛋白质相互作用对于心脏功能至关重要，但在心力衰竭发展过程中，单个RNA结合蛋白的活性如何通过心肌细胞中的信号级联进行调节尚不清楚。雷帕霉素激酶的机制靶标是控制心肌细胞中 mRNA 翻译的中央信号传导中枢；然而，mTOR 信号传导与心脏中 RNA 结合蛋白之间的直接联系尚未建立。综合转录组和翻译组分析揭示了早期病理重塑过程中 RNA 结合蛋白 Ybx1 依赖于 mTOR 的翻译上调，与 mRNA 水平无关。Ybx1 通过调节蛋白质合成是病理性心肌细胞生长所必需的。为了确定 Ybx1 如何调节细胞生长和蛋白质合成的分子机制，我们鉴定了与 Ybx1 结合的 mRNA。我们发现真核延伸因子 2 (Eef2) mRNA 与 Ybx1 结合，并且其翻译在心脏肥大期间依赖于 Ybx1 表达而上调。Eef2本身足以通过增加整体蛋白质翻译来驱动病理生长。最后，体内 Ybx1 耗竭在病理性心脏肥大期间保留了心脏功能。因此，mTORC1 的激活将病理信号级联与通过激活 Ybx1 改变的基因表达调控联系起来，而 Ybx1 反过来又通过增加 Eef2 的表达来促进翻译。