AUF1 modulates TGF-β signal in renal tubular epithelial cells via post-transcriptional regulation of Nedd4L expression.
AUF1 modulates TGF-β signal in renal tubular epithelial cells via post-transcriptional regulation of Nedd4L expression.
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AUF1 通过转录后调节 Nedd4L 表达来调节肾小管上皮细胞中的 TGF-β 信号
DOI：
10.1016/j.bbamcr.2017.10.001
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发表时间：
2018
影响因子：
5.1
通讯作者：
Du Zhen-Xian
中科院分区：
文献类型：
--
作者：
Yan Jing;Du Feng;Li Sheng-Dong;Yuan Ye;Jiang Jing-Yi;Li Si;Li Xin-Yu;Du Zhen-Xian
转录后调控过程在肾脏疾病的发病机制中起重要作用。富含AU的元件RNA结合蛋白（AUF 1）与3′UTR中含有富含AU的元件（战神）的mRNA相互作用并使其不稳定。目前的研究表明，AUF 1在单侧输尿管梗阻（UUO）动物模型中增加。虽然在正常条件下，HK 2细胞的增殖和迁移不受AUF 1下调的影响，但TGF-β介导的增殖抑制和迁移促进作用显著受损。在机制上，AUF 1下调通过在转录后水平增加其E3连接酶Nedd 4L来降低磷酸化Smad 2/3。此外，目前的研究将Nedd 4L确定为以前未报告的AUF 1靶点。AUF 1通过与Nedd 4L mRNA的3 'UTR中的战神相互作用在转录后水平调节Nedd 4L的表达。总之，目前的研究表明，AUF 1可能是通过Nedd 4L的转录后调节来调节TGF-β信号转导的肾小管间质纤维化的潜在参与者。
Posttranscriptional regulation process plays important roles in renal disease pathogenesis. AU-rich element RNA-binding protein (AUF1) interacts with and destabilizes mRNAs containing AU-rich elements (AREs) in their 3′UTR. The current study demonstrated that AUF1 was increased in unilateral ureteral obstruction (UUO) animal models. While proliferation and migration of HK2 cells was unaltered by AUF1 downregulation under normal condition, proliferative inhibition and migratory promotion mediated by TGF-β was significantly compromised. Mechanically, AUF1 downregulation decreased phosphorylated Smad2/3 via increasing their E3 ligase Nedd4L at the posttranscriptional level. In addition, the current study identified Nedd4L as a previously unreported target of AUF1. AUF1 regulates Nedd4L expression at the posttranscriptional level by interaction with AREs in the 3’UTR of the Nedd4L mRNA. Collectively, the current study indicates that AUF1 might be a potential player in renal tubulointerstitial fibrosis through modulation of TGF-β signal transduction via posttranscriptional regulation of Nedd4L.