HuR-Dependent Cooperative Export of miRNAs From Activated Macrophages

miRNA export is a regulated process vital for maintaining balanced miRNA levels and target gene expression in metazoan cells. RNA-interacting proteins finely adjust the selectivity and specificity of miRNA export, ensuring context-dependent optimal extracellular export of gene-repressive miRNAs in higher eukaryotes. Our findings reveal that activated macrophage cells export miRNAs in a cooperative manner, where elevated expression of miR-122 can significantly enhance the export of miR-146a and selective others. We predict and observe that the cooperative export of repressive miRNAs achieves synchronized upregulation of pro-inflammatory targets in activated macrophage cells. Exploring the molecular basis of this event, we have noted the co-entry of miRNAs into endosomes for their extracellular export, highlighting the selective and cooperative nature of endosome targeting of miRNAs. HuR, a miRNA-binding protein crucial for selectively exporting specific sets of miRNAs from various cell types, facilitates cooperative miRNA entry into endosomes both in the in vivo and in vitro assay conditions. A catalytic amount of high-affinity miR-122 enhances HuR’s binding to low-affinity miR-146a, facilitating the efficient endosomal compartmentalization of both miRNAs for their co-export via extracellular vesicles (EVs).