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The NF90-NF45 Complex Functions as a Negative Regulator in the MicroRNA Processing Pathway

机译：NF90-NF45复合体在MicroRNA加工途径中起负调控作用

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The positive regulatory machinery in the microRNA (miRNA) processing pathway is relatively well characterized, but negative regulation of the pathway is largely unknown. Here we show that a complex of nuclear factor 90 (NF90) and NF45 proteins functions as a negative regulator in miRNA biogenesis. Primary miRNA (pri-miRNA) processing into precursor miRNA (pre-miRNA) was inhibited by overexpression of the NF90 and NF45 proteins, and considerable amounts of pri-miRNAs accumulated in cells coexpressing NF90 and NF45. Treatment of cells overexpressing NF90 and NF45 with an RNA polymerase II inhibitor, α-amanitin, did not reduce the amounts of pri-miRNAs, suggesting that the accumulation of pri-miRNAs is not due to transcriptional activation. In addition, the NF90 and NF45 complex was not found to interact with the Microprocessor complex, which is a processing factor of pri-miRNAs, but was found to bind endogenous pri-miRNAs. NF90-NF45 exhibited higher binding activity for pri-let-7a than pri-miR-21. Of note, depletion of NF90 caused a reduction of pri-let-7a and an increase of mature let-7a miRNA, which has a potent antiproliferative activity, and caused growth suppression of transformed cells. These findings suggest that the association of the NF90-NF45 complex with pri-miRNAs impairs access of the Microprocessor complex to the pri-miRNAs, resulting in a reduction of mature miRNA production.
机译：microRNA（miRNA）加工途径中的阳性调控机制相对较好，但该途径的阴性调控尚不清楚。在这里，我们显示核因子90（NF90）和NF45蛋白的复合物在miRNA生物发生中起负调控作用。原代miRNA（pri-miRNA）加工成前体miRNA（pre-miRNA）被NF90和NF45蛋白的过表达抑制，并且大量的pri-miRNA积聚在共表达NF90和NF45的细胞中。用RNA聚合酶II抑制剂α-amanitin处理过表达NF90和NF45的细胞不会减少pri-miRNA的数量，这表明pri-miRNA的积累不是由于转录激活。此外，未发现NF90和NF45复合物与微处理器复合物相互作用，后者是pri-miRNA的加工因子，但可与内源性pri-miRNA结合。 NF90-NF45对pri-let-7a的结合活性高于pri-miR-21。值得注意的是，NF90的消耗导致pri-let-7a的减少和成熟的let-7a miRNA的增加（具有强大的抗增殖活性），并导致转化细胞的生长受到抑制。这些发现表明，NF90-NF45复合物与pri-miRNA的结合会损害微处理器复合物对pri-miRNA的进入，从而降低成熟miRNA的产生。

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