The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling
The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling
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DOI：
10.1074/jbc.m117.786764
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发表时间：
2017-09-15
影响因子：
4.8
通讯作者：
Frey, Norbert
中科院分区：
文献类型：
--
作者：
Dierck, Franziska;Kuhn, Christian;Frey, Norbert
Z盘是肌节外侧边缘的结构组件，对心肌和骨骼肌的机械稳定性和收缩性都很重要。值得注意的是，肌节Z盘也代表心肌细胞功能和信号传导的节点。许多z盘蛋白的突变与心肌病和肌肉疾病相关。为了鉴定可能导致心脏疾病的其他z盘蛋白，我们采用了对心脏富集cDNA的计算机筛选。该筛选产生了一种以前未表征的蛋白质，称为心脏富集FHL 2相互作用蛋白（CEFIP），其表现出心脏和骨骼肌特异性表达谱。重要的是，CEFIP位于z盘，并在几种心肌病模型中上调。我们还发现CEFIP过表达诱导胎儿基因程序和心肌细胞肥大。酵母双杂交筛选显示CEFIP与钙调神经磷酸酶结合蛋白4个半LIM结构域2（FHL 2）相互作用。因为FHL 2结合钙调磷酸酶，一种控制肥大信号传导的磷酸酶，我们研究了CEFIP对钙调磷酸酶/活化T细胞核因子（NFAT）通路的影响。这些实验表明，CEFIP过表达进一步增强钙调神经磷酸酶依赖性肥大信号转导，其敲低抑制肥大和钙调神经磷酸酶/ NFAT活性。总之，我们报告了一个以前未知的蛋白CEFIP，调节心肌细胞中的钙调神经磷酸酶/ NFAT信号，这一发现可能与心肌病的发病机制有关。
The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z-disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs. This screen yielded a previously uncharacterized protein named cardiac-enriched FHL2-interacting protein (CEFIP), which exhibited a heart-and skeletal muscle-specific expression profile. Importantly, CEFIP was located at the z-disc and was up-regulated in several models of cardiomyopathy. We also found that CEFIP overexpression induced the fetal gene program and cardiomyocyte hypertrophy. Yeast two-hybrid screens revealed that CEFIP interacts with the calcineurin-binding protein four and a half LIM domains 2 (FHL2). Because FHL2 binds calcineurin, a phosphatase controlling hypertrophic signaling, we examined the effects of CEFIP on the calcineurin/ nuclear factor of activated T-cell (NFAT) pathway. These experiments revealed that CEFIP overexpression further enhances calcineurin-dependent hypertrophic signal transduction, and its knockdown repressed hypertrophy and calcineurin/ NFAT activity. In summary, we report on a previously uncharacterized protein CEFIP that modulates calcineurin/ NFAT signaling in cardiomyocytes, a finding with possible implications for the pathogenesis of cardiomyopathy.