Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex networks that regulate cell differentiation, development and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of the control of miRNA function. Here, we review the mechanisms that modulate miRNA activity, stability and cellular localization through alternative processing and maturation, sequence editing, post-translational modifications of Argonaute proteins, viral factors, transport from the cytoplasm and regulation of miRNA–target interactions. We conclude by discussing intriguing, unresolved research questions.
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L.F.R.G. is supported by an Advanced Postdoc Mobility fellowship from the Swiss National Science Foundation, project number P300PA_177860. I.J.M. is supported by US National Institutes of Health grants R01-GM104475 and R01-GM115649.
Nature Reviews Molecular Cell Biology thanks A. Pasquinelli and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Variant forms of a canonical miRNA, generated by alternative cleavage during biogenesis, RNA editing or non-templated nucleotide addition.
- Guide strand
The strand in the mature miRNA duplex that is loaded into an Argonaute protein and used to identify complementary sites in target mRNAs.
A stable state in a system that is not the state of least energy.
- mRNA decay
Controlled mRNA degradation, usually starting with deadenylation, through either 3′–5′ exonucleolytic processing or decapping and 5′–3′ exonucleolytic processing.
- Trp-binding pockets
AGO possesses three pockets located in the PIWI domain, which bind tryptophan and mediate the interaction with GW182.
- miRNA clusters
Multiple miRNAs located in close proximity on the genome and transcribed as a single primary miRNA.
- Multivalent protein interactions
Protein–protein interactions mediated by multiple, often fairly weak binding events or points of contact.
- Seedless targets
miRNA targets with considerably reduced complementarity to the miRNA seed.
- Multivesicular endosomes
Type of late endosome that contains intraluminal vesicles formed by budding into the lumen of the endosome. Their content can be degraded by fusion with lysosomes or released into the extracellular space through fusion with the cell membrane.
Type of extracellular vesicle, ~50–150 nm in diameter, that contains proteins, lipids and RNA and can carry cargo to target cells.
- Stress granules
Following global translation shutdown during the cellular stress response, cytoplasmic granules form, which are composed of non-translating mRNAs, translation initiation factors and regulatory proteins.
- PAM2 motif
Poly(A) binding protein interacting motif 2 mediates the interaction between GW182 and PABP.
- miRNA sponges
Transcripts that contain multiple target sites for a specific miRNA and bind miRNAs, thereby derepressing the miRNA target mRNAs.
- Small nuclear RNAs
Small non-coding RNAs in the nucleus that form complexes with proteins and are part of the splicing machinery.
- Circulating miRNAs
miRNAs present in circulation and found either as AGO–miRNA complexes or as cargo of vesicles (exosomes).
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