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Small RNAs break out: the molecular cell biology of mobile small RNAs

Nature Reviews Molecular Cell Biology volume 15, pages 525–535 (2014)Cite this article

Subjects

Key Points

  • Small RNAs can move between cells and function at transcriptional and post-transcriptional levels to transmit gene regulatory information.

  • In plants, both 24-nucleotide-long (24-nt-long) and 21-nt-long siRNA duplexes are able to move from cell to cell over short ranges and over long distances through the phloem. However, whether the small RNAs can transmit information may depend on the recipient cell.

  • In Caenorhabditis elegans, specific channel proteins are required for small RNA mobility, but their mechanisms are still unclear.

  • Mobile RNAs can be inherited from one generation to the next and can move from one organism to another, even crossing species barriers.

  • There is evidence that small RNAs are secreted from mammalian cells, but their functional importance is still unclear.

Abstract

Small RNAs that function in a non-cell autonomous manner are becoming increasingly recognized as regulatory molecules with the potential to transmit information between cells, organisms and species. In plants and nematodes, small RNA mobility can be genetically dissected to provide information about the nature of the mobile RNA species, their distribution in the organism and inside cells, as well as the cellular machinery required for mobility, including channel proteins and cellular trafficking factors. Mobile RNAs function in antiviral defence, cell signalling and gene expression regulation, and might also mediate transgenerational epigenetic inheritance.

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Figure 1: Long-range transport from the shoot to the root in plants.
Figure 2: Possible roles for SID-1 in Caenorhabditis elegans small RNA transport.
Figure 3: The cell biology of mobile small RNAs.
Figure 4: Transgenerational epigenetic inheritance mediated by small RNAs and epigenetic marks in Caenorhabditis elegans.

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Acknowledgements

The authors thank members of the Miska laboratory for helpful discussions. P.S. was funded by a Gonville and Caius College Research Fellowship. Work in the Miska laboratory was funded by Cancer Research UK and the Wellcome Trust.

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  1. Gurdon Institute and Department of Genetics, University of Cambridge, The Henry Wellcome Building of Cancer and Developmental Biology, Tennis Court Road, Cambridge, CB2 1QN, UK

    Peter Sarkies & Eric A. Miska

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  1. Peter Sarkies
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  2. Eric A. Miska
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Correspondence to Peter Sarkies or Eric A. Miska.

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Supplementary information

Supplementary information S1 (box)

Antiviral RNAi in mammals (PDF 232 kb)

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Glossary

microRNAs

(miRNAs). RNAs that are ∼20–24 nucleotides in length and derived from specific endogenous loci. They are transcribed to form hairpin precursors that are cleaved to result in the final mature miRNA and miRNA* (corresponding to the more and less abundant RNAs, respectively) sequences.

Grafting

A technique widely used in agriculture and plant research that enables the stem of one plant to be joined to the roots of another. Vessels such as the xylem and the phloem fuse to enable the transfer of material between the two parts of the plant, enabling the grafted plant to survive and grow healthily.

Scion

A detached portion of a plant (for example, a bud or a shoot) joined to a stock in grafting experiments and usually only providing aerial parts to a graft.

Co-suppression

Discovered in plants, co-suppression occurs when a transgene can cause silencing of the endogenous copies of the homologous gene. Co-suppression is caused by small RNAs made against the transgene that can function in trans to silence endogenous loci.

Phloem

In vascular plants, the phloem is the main nutrient transport system, which carries organic nutrients (mostly sucrose- containing fluids) from tissues where they are synthesized ('source') to other tissues where they are needed ('sink').

Agrobacterium tumefaciens

A soil-dwelling bacterium that naturally infects plants to form crown gall tumours by inserting an invading DNA sequence (called T-DNA) into the plant genome. In the laboratory, engineered versions of A. tumefaciens can be used to insert transgenes of interest into plant cells.

Plasmodesmata

Large channels between adjacent plant cells that are directly formed by fusion of the cell membranes. They traverse the cell walls, to enable flow between the cytoplasm, and are typically around 50 nm in diameter (large enough to enable protein traffic).

Dicer enzyme

These enzymes are members of the class II subgroup of ribonuclease III enzymes that are found across Eukarya and function to generate both microRNAs and siRNAs through cleavage of precursors containing double-stranded regions. They are known as Dicer-like enzymes in plants.

Argonaute protein

(AGO protein). A member of a family of binding partners and effectors for many types of small RNA including those generated by Dicer but also PIWI-interacting RNAs (piRNAs) and other Dicer- independent small RNAs. Typically, AGO proteins, in conjunction with accessory proteins and their small RNA cofactors, form RNA-induced silencing complexes to bring about target gene silencing.

Sieve cells

Specialized cells lacking a nucleus that enable the flow through the phloem between enlarged plasmodesmata.

GW182

An accessory protein for Argonaute-silencing proteins, characterized by multiple Trp-Gly repeats.

ABC transporter

A widely conserved group of transmembrane proteins that power the transport of a range of different substrates through the hydrolysis of ATP.

Suppressors of silencing

Virally encoded proteins that enable viruses to counter RNAi defence mechanisms. Most examples of these proteins known so far derive from plant viruses and inhibit RNAi at different stages in the pathway.

Positive-strand RNA virus

The RNA genome of this virus encodes the sense strand of the viral proteins, thus it can be directly translated to produce a coding sequence. This is in contrast to negative-strand viruses, which must be copied to produce the positive strand before translation can occur.

Interferon response

A key component of the mammalian innate immune pathway. It involves transcriptional activation of interferon genes, which in turn induce intracellular and intercellular effects.

Vegetative nucleus

One of the two nuclei in the plant pollen. It does not contribute DNA to the next generation but instead forms the endosperm after fertilization, which provides nourishment to the developing seed.

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Sarkies, P., Miska, E. Small RNAs break out: the molecular cell biology of mobile small RNAs. Nat Rev Mol Cell Biol 15, 525–535 (2014). https://doi.org/10.1038/nrm3840

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