Fig. 1

The secretion and uptake processes of extracellular miRNAs. After being transcribed in the nucleus, exported to the cytoplasm and processed to the mature form, miRNAs can be loaded into the RNA-induced silencing complex (RISC) and then target mRNAs, inducing mRNA degradation or translational inhibition. They can also be packaged and secreted to the extracellular environment via three ways. (1) Some miRNAs with specific EXOmotifs can be recognized by sumoylated heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and, combining with this protein at these motifs, be incorporated into exosomes. Neutral sphingomyelinase 2 (nSMase2), a rate-limiting enzyme of ceramide biosynthesis, promotes the secretion of exosomal miRNAs. Additionally, phosphorylated pyruvate kinase type M2 (PKM2) can phosphorylate synaptosome-associated protein 23 (SNAP-23) to facilitate exosome release. (2) MiRNAs can be loaded into shedding vesicles and be secreted through blebbing and shedding from the plasma membrane, but the mechanisms are still unknown. Many microvesicle (MV)-encapsulated miRNAs are associated with RISC proteins such as AGO2, which may increase the resistance of the miRNAs to RNases and enhance extracellular miRNA function. (3) Conjunction with RNA-binding proteins, such as high-density lipoprotein (HDL), can stabilize extracellular miRNAs during their exportation. nSMase2 represses cellular export of miRNAs to HDL. Exosomes and shedding vesicles can be absorbed by recipient cells through endocytosis or direct fusion with the plasma membrane. HDL-associated miRNAs are taken up by recipient cells through binding to scavenger receptor BI (SR-BI) present at the recipient cellular membrane. MiRNAs in recipient cells can target mRNAs and regulate protein expression, thus influencing the physiological and pathological processes of recipient cells