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The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs
Michele Trabucchi1, Paola Briata2,5, MariaFlor Garcia-Mayoral3, Astrid D. Haase4, Witold Filipowicz4, Andres Ramos3, Roberto Gherzi2,5 & Michael G. Rosenfeld1,5
1 Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA
2 Istituto Nazionale per la Ricerca sul Cancro (IST), Largo R. Benzi, 10; 16132 Genova, Italy
3 Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK
4 Friedrich Miescher Institute for Biomedical Research, PO Box 2543, 4002 Basel, Switzerland
5 These authors contributed equally to this work.
Consistent with the role of microRNAs (s) in down-regulating gene expression by reducing the translation and/or stability of target messenger RNAs1, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer2, 3, 4. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes5, 6, 7, 8, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP, also known as KHSRP) interacts with single-strand AU-rich-element-containing mRNAs and is a key mediator of mRNA decay9, 10. Here we show in mammalian cells that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affect specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.
