microRNAs: critical regulators in Th17 cells and players in diseases

Abstract

microRNAs are a novel group of small, conserved, non-coding RNA molecules that are present in all species. These molecules post-transcriptionally regulate gene expression by targeting mRNAs for degradation or by repressing the translation of the mRNAs. A good understanding of miRNA-mediated gene regulation is critical to gain a comprehensive view of many physiological processes and disease states. Emerging evidence demonstrates that miRNAs play an important role in the differentiation and function of the adaptive immune system. This review provides an overview of the diverse functions of miRNAs in modulating immune responses and in immune cell development, particularly the development of Th17 cells, and explores the involvement of miRNAs in several autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and diabetes.

Figure 1

MicroRNA biogenesis and the mechanism of microRNA-mediated gene silencing. MicroRNAs (miRNAs) are short, double-stranded RNA molecules of approximately 19–23 nt in length. The primary transcripts of miRNAs (pri-miRNAs) are transcribed by RNA polymerase II from varied genomic loci. Primary miRNA transcripts are processed into precursor miRNA (pre-miRNA) stem-loops of approximately 60 nt in length by the nuclear RNase III enzyme, Drosha, which is assisted by DiGeorge syndrome critical region gene 8 (DGCR8). These pre-miRNAs are then exported into the cytoplasm by a Ran-GTP-dependent nuclear transport receptor, exportin 5, where they are further processed into approximately 22-nt miRNA duplexes by the type III RNase, Dicer. The final step of miRNA maturation is the selective loading of the functional strand of the small RNA duplex into the RNA-induced silencing complex (RISC). Mature miRNAs then guide the complex to their complementary mRNAs for regulation of gene expression. Regulation is be mediated by various mechanisms including repression of translation, mRNA cleavage and deadenylation. Ran-GTP, ras-related nuclear protein-guanosine triphosphate.

Figure 2

Roles of miRNAs in the development and function of the adaptive immune system. See text for detailed explanations. CLP, common lymphocyte progenitor; DC, dendritic cells; Ets-1, E26 transformation-specific-1; HSC, hematopoietic stem cells; Treg, regulatory T cell.