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LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages

Tina Ruggiero^*,1, Michele Trabucchi^,1, Francesca De Santa, Simona Zupo, Brian D. Harfe^||, Michael T. McManus^¶, M. Geoff Rosenfeld, Paola Briata^,2,3 and Roberto Gherzi^,2,3

^* RNA Technology Laboratory, Centro Biotecnologie Avanzate, Genoa, Italy;

Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California, USA;

Department of Experimental Oncology, European Institute of Oncology, Milan, Italy;

Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;

^|| Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA; and

^¶ UCSF Diabetes Center, Department of Microbiology and Immunology, University of California, San Francisco, California, USA

³ Correspondence: Gene Expression Regulation Laboratory, National Cancer Institute IST, Largo R. Benzi, 10, 16132 Genova, Italy. E-mail: R.G., rgherzi{at}ucsd.edu; P.B., paola.briata{at}istge.it

The importance of post-transcriptional mechanisms for the regulation of the homoeostasis of the immune system and the response to challenge by microorganisms is becoming increasingly appreciated. We investigated the contribution of microRNAs (miRNAs) to macrophage activation induced by lipopolysaccharide (LPS). We first observed that Dicer knockout in bone marrow-derived macrophages (BMDMs) increases the LPS-induced expression of some inflammation mediators. miRNA microarray analysis in BMDMs revealed that LPS significantly induces the expression of a single miRNA, miR-155, and this induction depends on enhanced miR-155 maturation from its precursors. The single-strand RNA-binding protein KH-type splicing regulatory protein (KSRP) binds to the terminal loop of miR-155 precursors and promotes their maturation. Both inhibition of miR-155 and KSRP knockdown enhance the LPS-induced expression of select inflammation mediators, and the effect of KSRP knockdown is reverted by mature miR-155. Our studies unveil the existence of an LPS-dependent post-transcriptional regulation of miR-155 biogenesis. Once induced, miR-155 finely tunes the expression of select inflammation mediators in response to LPS.—Ruggiero, T., Trabucchi, M., De Santa, F., Zupo, S., Harfe, B. D., McManus, M. T., Rosenfeld, M. G., Briata, P., Gherzi, R. LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages.

Key Words: RNA-binding protein • post-transcriptional regulation of gene expression • inflammation