NSun2 promotes cell migration through methylating autotaxin mRNA.
NSun2 promotes cell migration through methylating autotaxin mRNA.
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DOI：
10.1074/jbc.ra119.012009
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发表时间：
2020-12-25
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Xu X;Zhang Y;Zhang J;Zhang X
NSun 2是一种RNA甲基转移酶，将5-甲基胞嘧啶引入tRNA、mRNA和非编码RNA，从而影响这些RNA的水平或功能。自分泌运动因子（ATX）是一种分泌型糖蛋白，被认为是将溶血磷脂酰胆碱转化为溶血磷脂酸（LPA）的关键因子。ATX-LPA轴在细胞存活、迁移、增殖和分化中发挥多种生物学作用。在这里，我们表明，NSun 2是通过甲基化ATX mRNA参与细胞迁移的调节。在人脑胶质瘤细胞系U87中，NSun 2的敲低降低了ATX蛋白水平，而NSun 2的过表达升高了ATX蛋白水平。然而，NSun 2的过表达或敲低均不改变ATX mRNA水平。进一步的研究表明，NSun 2在体内外均可使ATX mRNA的3′-UTR在胞嘧啶2756位发生甲基化。NSun 2甲基化增强ATX mRNA翻译。此外，NSun 2介导的5-甲基胞嘧啶甲基化促进ATX mRNA从细胞核输出到细胞质中，这是一种依赖于NADPH的方式。NSun 2的敲除抑制了U87细胞的迁移，这是通过添加LPA来拯救的。总之，我们确定NSun 2介导的ATX mRNA甲基化是ATX调控的一种新机制。
NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3′-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.