Abstract
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.
Highlights
MRNA methylation is an important modification type in physiological and pathological processes
To test whether m6A or m5C modification exists in ATX mRNA, ribonucleoprotein-immunoprecipitation (RNP-IP) assays were performed by using anti-m5C or -m6A antibody
Because NSun2 is a main mRNA methyltransferase catalyzing m5C formation, we further tested whether NSun2 could interact with ATX mRNA
Summary
MRNA methylation is an important modification type in physiological and pathological processes. NSun2-mediated mRNA methylation enhances the translation of CDK1, E2F3, and p21 proteins to promote cell proliferation [8, 9]. We show that RNA methyltransferase NSun2 catalyzes the methylation of ATX mRNA 39UTR at C2756.
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