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The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs

Nature volume 459, pages 1010–1014 (2009)Cite this article

Abstract

Consistent with the role of microRNAs (miRNAs) 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.

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Figure 1: KSRP, a component of Dicer complex, interacts with the TL of pre-let-7a-1.
Figure 2: KSRP regulates pre-let-7a-1 processing and controls the expression of certain miRNAs.
Figure 3: KSRP is a component of the microprocessor complex, interacts with pri-let-7a-1 favouring its processing, and is required for interaction of both Drosha and Dicer complexes with let-7a precursors.
Figure 4: KSRP affects let-7-regulated cell proliferation and is involved in Lin28-regulated maturation of let-7g in P19 cells.

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Acknowledgements

We thank V. Narry Kim, T. C. Hobman, I. G. Macara, D. Srivastava and J. G. Belasco for reagents, G. Corte for sharing laboratory facilities and critical reading, Y. T. Liu for use of the microarray facility, M. Ponassi and C. Nelson for technical assistance, I. Diaz-Moreno, M. Doyle, S. Martin and D. Hollingworth for discussions and reagents, and A. Pasquinelli and A. De Flora for comments and discussions. Part of the studies has been conducted in the laboratories and facilities of the Centro Biotecnologie Avanzate (CBA, Genova, Italy). M.G.R. is an investigator with the Howard Hughes Medical Institute. M.T. is supported by a post-doctoral fellowship from the Italian Telethon Foundation. This work has been partly supported by grants from Italian ISS (527B/2B/6), AIRC and CIPE 2007 to R.G., ISS (526D/39) to P.B., the EC FP6 Program Sirocco to W.F. and NIH grants DK018477, DK39949 and HL065445 to M.G.R. P.B. is recipient of a Senior Scholar Consultancy grant from AICF. Structural work on KSRP–RNA interaction is supported by grant WT022088MA from the Wellcome Trust. NMR spectra were recorded at the MRC Biomedical NMR Centre, London. The Friedrich Miescher Institute is supported by the Novartis Research Foundation.

Author information

Author notes

  1. Paola Briata, Roberto Gherzi and Michael G. Rosenfeld: These authors contributed equally to this work.

Authors and Affiliations

  1. Department and School of Medicine, Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA,

    Michele Trabucchi & Michael G. Rosenfeld

  2. Istituto Nazionale per la Ricerca sul Cancro (IST), Largo R. Benzi, 10,

    Paola Briata & Roberto Gherzi

  3. 16132 Genova, Italy,

    Paola Briata & Roberto Gherzi

  4. Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK,

    MariaFlor Garcia-Mayoral & Andres Ramos

  5. Friedrich Miescher Institute for Biomedical Research, PO Box 2543, 4002 Basel, Switzerland ,

    Astrid D. Haase & Witold Filipowicz

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  1. Michele Trabucchi
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Correspondence to Andres Ramos, Roberto Gherzi or Michael G. Rosenfeld.

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Trabucchi, M., Briata, P., Garcia-Mayoral, M. et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459, 1010–1014 (2009). https://doi.org/10.1038/nature08025

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