Figure 1

Biogenesis of circulating miRNAs. miRNAs are transcribed in the nucleus as pri-miRNAs with 5′-caps and 3'-polyA tails. Drosha removes the cap and polyA tail to generate pre- miRNAs, which are exported from the nucleus via Exportin 5. In the cytoplasm Dicer processes the pre-miRNA to mature miRNAs. Pre-miRNA and mature miRNA can (a) bind to RNA-binding proteins to be directly excreted from the cell, (b) packaged into microvesicles or (c) packed into exosomes and multi-vesicular bodies where the exosomes are then released. Pre-miRNA and mature miRNAs are taken into the bloodstream by endocytosis, binding to receptors or via membrane fusion.