The Whereabouts of microRNA Actions: Cytoplasm and Beyond

MicroRNAs (miRNAs) are a conserved class of approximately 22 nucleotide (nt) short noncoding RNAs that normally silence gene expression via translational repression and/or degradation of targeted mRNAs in plants and animals. Identifying the whereabouts of miRNAs potentially informs miRNA functions, some of which are perhaps specialized to specific cellular compartments. In this review, the significance of miRNA localizations in the cytoplasm, including those at RNA granules and endomembranes, and the export of miRNAs to extracellular space will be discussed. How miRNA localizations and functions are regulated by protein modifications on the core miRNA-binding protein Argonaute (AGO) during normal and stress conditions will be explored, and in conclusion new AGO partners, non-AGO miRNA-binding proteins, and the emergent understanding of miRNAs found in the nucleoplasm, nucleoli, and mitochondria will be discussed. Mature miRNAs localize in multiple subcellular locations in the cytoplasm, such as RNA granules, endomembranes, and mitochondria, and are secreted out of cells via exosomes.Recent studies have revealed that mature miRNAs can also localize to the nucleus, where they could function in epigenetic regulation.The distributions of canonical and noncanonical forms of miRNA-induced silencing complexes suggest that different subcellular locations are required for the processing and degradation of miRNA itself, or for silencing or activation of miRNA targets.These subcellular distributions are differentially regulated by post-translational modifications as a function of cellular conditions, but one major question is whether such location-specific miRNAs are physiologically relevant.