RNA-binding Protein Musashi Homologue 1 Regulates Kidney Fibrosis by Translational Inhibition of p21 and Numb mRNA
RNA-binding Protein Musashi Homologue 1 Regulates Kidney Fibrosis by Translational Inhibition of p21 and Numb mRNA
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DOI：
10.1074/jbc.m115.713289
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发表时间：
2016-07-01
影响因子：
4.8
通讯作者：
Vaidya, Vishal S.
中科院分区：
文献类型：
--
作者：
Jadhav, Shreyas;Ajay, Amrendra K.;Vaidya, Vishal S.
rna结合蛋白（rna binding protein, rbp）被认为是关键的转录后调控因子，不仅调节生物发育过程中基因的时空表达，还调节疾病的发病机制。关于rbp在调节肾纤维化中的潜在作用的信息非常有限，肾纤维化是慢性肾脏疾病的主要标志。在这里，我们报告了一种涉及RBP的肾纤维化新机制，即在小管上皮细胞中表达的Musashi同源物1 （Msi1）。使用两种机制不同的肾纤维化小鼠模型，我们发现Msi1蛋白水平在纤维化后的肾脏中显著下调。我们发现Msi1通过负调控其靶mrna p21和Numb的翻译发挥作用，其蛋白水平在肾纤维化中显着升高。此外，Msi1在肾上皮细胞中的过表达和敲低导致p21和麻木介导的细胞周期阻滞。此外，我们观察到Numb在纤维化肾脏中失去了其特有的膜定位，因此可能无法抑制Notch导致小管细胞死亡。油酸是已知的Msi1抑制剂，与对照组相比，注射油酸后单侧输尿管梗阻手术小鼠的纤维化增强，表明抑制Msi1活性使小鼠更容易发生纤维化。鉴于脂肪酸代谢失调在肾纤维化中起关键作用，这些结果表明脂肪酸与Msi1（一种rna结合蛋白）在肾纤维化中存在新的联系。
RNA-binding proteins (RBPs) are recognized as key posttranscriptional regulators that not only modulate the spatiotemporal expression of genes during organism development but also regulate disease pathogenesis. Very limited information exists on the potential role of RBPs in modulating kidney fibrosis, which is a major hallmark of chronic kidney disease. Here, we report a novel mechanism in kidney fibrosis involving a RBP, Musashi homologue 1 (Msi1), which is expressed in tubular epithelial cells. Using two mechanistically distinct mouse models of kidney fibrosis, we show that Msi1 protein levels are significantly down-regulated in the kidneys following fibrosis. We found that Msi1 functions by negatively regulating the translation of its target mRNAs, p21 and Numb, whose protein levels are markedly increased in kidney fibrosis. Also, Msi1 overexpression and knockdown in kidney epithelial cells cause p21- and Numb-mediated cell cycle arrest. Furthermore, we observed that Numb looses its characteristic membrane localization in fibrotic kidneys and therefore is likely unable to inhibit Notch resulting in tubular cell death. Oleic acid is a known inhibitor of Msi1 and injecting oleic acid followed by unilateral ureteral obstruction surgery in mice resulted in enhanced fibrosis compared with the control group, indicating that inhibiting Msi1 activity renders the mice more susceptible to fibrosis. Given that deregulated fatty acid metabolism plays a key role in kidney fibrosis, these results demonstrate a novel connection between fatty acid and Msi1, an RNA-binding protein, in kidney fibrosis.