微小RNA（miRNA）是首先在秀丽线虫中发现的一类小的非编码RNA。lin-28/let-7路径是调控缝线细胞严格发育时序的途径，我们发现秀丽线虫的PPK-1在其中发挥作用。在秀丽线虫和人类细胞中，PPK-1/PIP5K1A调控let-7 miRNA水平。我们在人类细胞中进一步研究了这一机制，发现PIP5K1A在细胞核与核出口蛋白XPO5相互作用，通过阻断XPO5与前体let-7 miRNA的结合来调节成熟miRNA水平。此外，我们证明了PIP5K1A的这一作用与其激酶活性无关。我们的研究揭示了PIP5K1A与miRNA生物合成之间的直接联系。鉴于miRNA在多种疾病中，包括癌症中的作用，这一新发现可能带来新的治疗机会。© 2023作者. 由牛津大学出版社代表<核酸研究>出版。

MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.