The Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, 361100, P.R. China.
Fujian Key Laboratory of Organ and Tissue Regeneration, Medical College, Xiamen University, 361100, P.R. China.
Sci Rep. 2017 Mar 21;7:44870. doi: 10.1038/srep44870.
RNA-binding protein Rbm24 is a key regulator of heart development and required for sarcomere assembly and heart contractility. Yet, its underlying mechanism remains unclear. Here, we link serine/threonine kinase 38 (Stk38) signaling to the regulation of Rbm24 by showing that Rbm24 phosphorylation and its function could be modulated by Stk38. Using co-immunoprecipitation coupled with mass spectrometry technique, we identified Stk38 as an endogenous binding partner of Rbm24. Stk38 knockdown resulted in decreased Rbm24 protein level in cardiomyocytes. Further studies using Stk38 kinase inhibitor or activator showed that Rbm24 protein stability was regulated in a kinase activity-dependent manner. Deficiency of Stk38 caused reduction of sarcomere proteins and disarrangement of sarcomere, suggesting that Stk38 is essential for Rbm24 to regulate sarcomere assembly. Our results revealed that Stk38 kinase catalyzes the phosphorylation of Rbm24 during sarcomerogensis and this orchestrates accurate sarcomere alignment. This furthers our understanding of the regulatory mechanism of cardiac sarcomere assembly in both physiologic and pathologic contexts, and uncovers a potential novel pathway to cardiomyopathy through modulating the Stk38/Rbm24 protein activity.
RNA 结合蛋白 Rbm24 是心脏发育的关键调节因子，对于肌节组装和心脏收缩性是必需的。然而，其潜在的机制尚不清楚。在这里，我们将丝氨酸/苏氨酸激酶 38（Stk38）信号与 Rbm24 的调节联系起来，表明 Stk38 可以调节 Rbm24 的磷酸化及其功能。通过共免疫沉淀结合质谱技术，我们鉴定出 Stk38 是 Rbm24 的内源性结合伴侣。Stk38 敲低导致心肌细胞中 Rbm24 蛋白水平降低。使用 Stk38 激酶抑制剂或激活剂的进一步研究表明，Rbm24 蛋白稳定性以激酶活性依赖性方式调节。Stk38 的缺乏导致肌节蛋白减少和肌节排列紊乱，表明 Stk38 对于 Rbm24 调节肌节组装是必需的。我们的结果表明，Stk38 激酶在肌节发生过程中催化 Rbm24 的磷酸化，这协调了肌节的准确排列。这进一步加深了我们对生理和病理条件下心脏肌节组装的调节机制的理解，并揭示了通过调节 Stk38/Rbm24 蛋白活性导致心肌病的潜在新途径。
