Autotaxin Expression Is Regulated at the Post-transcriptional Level by the RNA-binding Proteins HuR and AUF1
Autotaxin Expression Is Regulated at the Post-transcriptional Level by the RNA-binding Proteins HuR and AUF1
复制标题
自分泌运动因子的表达在转录后水平由 RNA 结合蛋白 HuR 和 AUF1 调节。
DOI：
10.1074/jbc.m116.756908
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发表时间：
2016-12-09
影响因子：
4.8
通讯作者：
Zhang, Junjie
中科院分区：
文献类型：
--
作者：
Sun, Shuhong;Zhang, Xiaotian;Zhang, Junjie
自体趋化蛋白(ATX)是将溶血磷脂酰胆碱(LPC)转化为溶血磷脂酸(LPA)的关键酶，溶血磷脂酸是一种溶血磷脂介质，通过其特有的G蛋白偶联受体调节细胞活动。ATX-LPA轴在多种生理和病理过程中发挥着重要作用，特别是在炎症和癌症的发生发展过程中。虽然ATX的转录调控已经得到了广泛的研究，但ATX的转录后调控在很大程度上是未知的。在本研究中，我们在ATX mRNA3‘-非翻译区(3’UTR)中发现了富含腺苷(AU)的保守元件。RNA结合蛋白HUR和AUF1直接与ATX基因3‘非编码区结合，对ATX的表达具有拮抗作用。HUR通过增加ATX mRNA的稳定性来促进ATX的表达，而AUF1通过促进ATX mRNA的衰退而抑制ATX的表达。HUR和AUF1参与了人结肠癌细胞和内毒素刺激的人单核细胞THP-1细胞ATX的调节。HUR基因敲除可抑制B16小鼠黑色素瘤细胞中ATX的表达，从而抑制细胞迁移。这一作用可被AUF1基因敲除以恢复ATX表达或被LPA加入所逆转。这些结果表明，Hur和AUF1对ATX表达的转录后调节调节了癌细胞的迁移。综上所述，我们确定HUR和AUF1是ATX表达的新的转录后调节因子，从而阐明了ATX-LPA轴的新调控机制。
Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a lysophospholipid mediator that regulates cellular activities through its specific G protein-coupled receptors. The ATX-LPA axis plays an important role in various physiological and pathological processes, especially in inflammation and cancer development. Although the transcriptional regulation of ATX has been widely studied, the post-transcriptional regulation of ATX is largely unknown. In this study, we identified conserved adenylate-uridylate (AU)-rich elements in the ATX mRNA 3'-untranslated region (3'UTR). The RNA-binding proteins HuR and AUF1 directly bound to the ATX mRNA 3'UTR and had antagonistic functions in ATX expression. HuR enhanced ATX expression by increasing ATX mRNA stability, whereas AUF1 suppressed ATX expression by promoting ATX mRNA decay. HuR and AUF1 were involved in ATX regulation in Colo320 human colon cancer cells and the LPS-stimulated human monocytic THP-1 cells. HuR knockdown suppressed ATX expression in B16 mouse melanoma cells, leading to inhibition of cell migration. This effect was reversed by AUF1 knockdown to recover ATX expression or by the addition of LPA. These results suggest that the post-transcriptional regulation of ATX expression by HuR and AUF1 modulates cancer cell migration. In summary, we identified HuR and AUF1 as novel post-transcriptional regulators of ATX expression, thereby elucidating a novel mechanism regulating the ATX-LPA axis.