Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5.
Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5.
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DOI：
10.1093/nar/gkad709
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发表时间：
2023-10-13
影响因子：
14.9
通讯作者：
Slack, Frank J.
中科院分区：
文献类型：
--
作者：
Li, Chun;Yoon, Bohyung;Stefani, Giovanni;Slack, Frank J.
MicroRNAs （miRNAs）是在秀丽隐杆线虫中首次发现的小的非编码rna。从秀丽隐杆线虫到人类，let-7 miRNA在序列、生物发生和功能上高度保守。在miRNA生物发生过程中，xpo5介导的pre-miRNA核输出是一个限速步骤，因此可能对miRNA水平的定量控制至关重要，但对其如何调控知之甚少。在这里，我们发现了脂质激酶PPK-1/PIP5K1A（磷脂酰肌醇-4-磷酸5激酶）在调节miRNA水平中的新作用。我们发现秀丽隐杆线虫PPK-1在lin-28/let-7异慢性通路中起作用，该通路调节缝细胞的严格发育时间。在秀丽隐杆线虫和人类细胞中，PPK-1/PIP5K1A调节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与细胞核中的核输出蛋白XPO5相互作用，通过阻断XPO5与pre-let-7 miRNA的结合来调节成熟miRNA的水平。此外，我们证明了PIP5K1A的这种作用是激酶无关的。我们的研究揭示了PIP5K1A与miRNA生物发生之间直接联系的新发现。鉴于mirna与包括癌症在内的多种疾病有关，这一新发现可能会带来新的治疗机会。
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.
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DOI：
10.4161/cc.29017
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Chu YD;Wang WC;Chen SA;Hsu YT;Yeh MW;Slack FJ;Chan SP
通讯作者：
Chan SP
DOI：
10.1261/rna.045542.114
发表时间：
2015-05
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Stefani G;Chen X;Zhao H;Slack FJ
通讯作者：
Slack FJ
影响因子：
4.1
作者：
Graf R;Munschauer M;Mastrobuoni G;Mayr F;Heinemann U;Kempa S;Rajewsky N;Landthaler M
通讯作者：
Landthaler M
影响因子：
9.2
作者：
Parry, Devin H.;Xu, Jinling;Ruvkun, Gary
通讯作者：
Ruvkun, Gary
影响因子：
4.8
作者：
Coppolino, MG;Dierckman, R;Grinstein, S
通讯作者：
Grinstein, S