MIR155 · microRNA-155 expression control and function in innate immune inflammatory response

MicroRNAs (miRNAs) are small non-coding RNAs which play critical roles in key biological processes, including immune response. miRNAs derive from transcripts (pri-miRNAs) which are processed by Drosha into intermediate hairpin precursors (pre-miRNAs). Pre-miRNAs are then processed by Dicer into mature forms of about 22 nucleotides. Mature miRNAs are loaded in the RNA-induced silencing complex (RISC) to mediate degradation and/or translation inhibition of specific target mRNAs. Many reports documented discrepancies in the levels of precursors and mature miRNAs indicating a wide potential for post-transcriptional control of miRNA expression. We recently discovered that the terminal loop structure of miRNA precursors plays a pivotal role as dock for co-activators of miRNA processing (e.g. KSRP) or co-repressors (e.g. Lin28), acting in a coordinated way to control miRNA biogenesis. Among the miRNAs post-transcriptionally regulated by KSRP we identified miR-155. miR-155 regulates both adaptive and innate immune responses. In macrophages, miR-155 maturation is induced upon lipopolysaccharide (LPS) stimulus. I hypothesize that a repressor complex is bound to pri-miR-155 in untreated macrophages to block the recruitment of KSRP and thus the maturation. LPS stimulus induces the dismissal of the repressor and the recruitment of the activator complex to pri-miR-155. Aims of my future work will be to identify in macrophages: i) the components of the regulatory complex(es) for miR-155 biogenesis; ii) the dynamics and the post-translational modifications that modulate the exchange between regulatory complexes; iii) novel miR-155 direct target mRNAs. This study will delineate the regulatory network that controls miR-155 maturation and function in macrophages allowing the design and the validation of tools capable of modulating it and, as a consequence, the magnitude of the innate immune inflammatory response.