Our research is focused on the molecular mechanisms underlying gene expression control at the post-transcriptional level in response to extracellular signals. Two post-transcriptional pathways mainly control the gene expression, namely microRNAs (miRNAs) and AU-rich element Mediated Degradation of mRNA (AMD).  MicroRNAs (miRNAs) are evolutionary conserved small non-coding RNAs, which  arise from processing of hairpin primary transcripts by two sequential RNAse III domain-containing enzymes, namely Drosha and Dicer, to generate a mature form of about 22 nucleotides. Mature miRNAs are loaded in the RNA-induced silencing complex (RISC), containing Argonaute 2, in order to mediate degradation and/or inhibition of translation of specific target mRNAs via Watson-Crick base pairing partial sequence complementary. Expression of many miRNAs is consistently tissue or developmental stage specific, and its deregulation is involved in numerous human diseases, including genetic disorders, such as chronic lymphocytic leukaemia. Besides miRNAs, AMD is another pathway aiming to post-trascriptionally control the gene expression. AMD promotes decay of unstable mRNAs which possess crucial biological functions, e.g. cyclins and B-catenin mRNAs. AMD requires at least three components, (i) an instability element, such as the Adenylate/uridylate−Rich Elements (ARE) located in the 3’ untranslated region (3’ UTR), (ii) ARE binding proteins (ARE−BPs), and (iii) two enzymes, the exosome and the deadenylation enzyme PARN.  ARE−BPs, such as AUF1, TTP, TIA-1, KSRP (KH-type splicing regulatory protein) promote decay of ARE containing RNAs, while HuR stabilizes them. Importantly, both miRNA and AMD pathways represent a very established cellular strategy that permits relatively quick changes in gene expression pattern in response to environmental or developmental stimuli.

Different reports pointed out the relevance of both transcriptional and post-transcriptional regulation of miRNAs expression demonstrating a plethora of regulatory options to differentially control miRNA levels. We have published a paper in Nature describing a novel mechanism of microRNA processing regulation. In particular, we showed that KSRP is an integral component of both Drosha and Dicer complexes and promotes the maturation of a subset of miRNA precursors. Our data indicate that activators of miRNA processing (KSRP and possibly additional RNA binding proteins) as well as repressors of miRNA processing (e.g. Lin28 for let-7 precursors), act in a coordinated way to convert cellular signals into changes in miRNA expression processing, providing the first rational basis to identify additional repressors and activators of miRNA biogenesis. Among miRNAs whose maturation is controlled by KSRP, we have found miR-155 (published in FASEB J), a microRNA that is up-regulated in immune cells upon microbial and inflammatory challenges. miR-155 regulates the magnitude of the innate inflammatory response by modulating different inflammatory transcripts. We found that LPS treatment regulates the maturation of miR-155 leaving unaffected pri-miR-155 transcription, indicating the existence of a LPS-induced and KSRP-dependent post-transcriptional regulation of miR-155 biogenesis. Together, these data infer a continuum of KSRP-dependent molecular strategies for RNA regulation: promoting in one hand the biogenesis of microRNAs and in the other hand the degradation of unstable mRNAs, in each case based on its versatile ability to recognize different classes of RNA motifs.