Resolving subcellular miRNA trafficking and turnover at single-molecule resolution
Open accessAbstract
Regulation of microRNA (miRNA) localization and stability is critical for their extensive cytoplasmic RNA silencing activity and emerging nuclear functions. Here, we have developed single-molecule fluorescence-based tools to assess the subcellular trafficking, integrity, and activity of miRNAs. We find that seed-matched RNA targets protect miRNAs against degradation and enhance their nuclear retention. While target-stabilized, functional, cytoplasmic miRNAs reside in high-molecular-weight complexes, nuclear miRNAs, as well as cytoplasmic miRNAs targeted by complementary anti-miRNAs, are sequestered stably within significantly lower-molecular-weight complexes and rendered repression incompetent. miRNA stability and activity depend on Argonaute protein abundance, whereas miRNA strand selection, unwinding, and nuclear retention depend on Argonaute identity. Taken together, our results show that miRNA degradation competes with Argonaute loading and target binding to control subcellular miRNA abundance for gene silencing surveillance. Probing single cells for miRNA activity, trafficking, and metabolism promises to facilitate screening for effective miRNA mimics and anti-miRNA drugs.
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Low molecular weight miRISC can interact with mRNAs within the nucleus and induce nuclear mRNA degradation.
“It has been reported that low molecular weight miRISC can interact with mRNAs within the nucleus and induce nuclear mRNA degradation, although the mechanism behind this is unclear (59, 61, 63).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [61]
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References 58 · Cited by 98
- Authors
- Pitchiaya, S., Heinicke, L. A., Park, J. I., Cameron, E. L., & Walter, N. G.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Walter, Nils G.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 19
- Issue
- 3
- Pages
- 630-642
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5482240
- OpenAlex
- W2605546706
- Cited by
- 98
- References
- 58
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 8 · 2020: 13 · 2019: 17 · 2018: 13 · 2017: 2
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (4T32GM008353, GM062357, R01 GM081025)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- miRNA stability, subcellular localization, Argonaute proteins, RNA silencing, nuclear retention, anti-miRNA, single-molecule fluorescence microscopy, miRNA mimics
- MeSH terms
- Single Molecule Imaging, Animals, Cell Count, Cell Nucleus, Humans, Models, Biological, RNA, Messenger, Subcellular Fractions, Reproducibility of Results, Molecular Probes, RNA Stability, RNA Transport, MicroRNAs, Intracellular Space, Cell Line, Tumor, Mice, Argonaute Proteins
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