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Juan Pablo Tosar1,2, Amy H Buck3
1Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay.
Abstract:
Despite a huge expansion in the last decades, several assumptions have directed, and perhaps pigeonholed, the evolution of the extracellular RNA (exRNA) field. For example, extracellular vesicles (EVs) have been assumed to be the main carriers of RNA molecules between cells. In parallel, microRNAs (miRNAs) have been assumed to be the main EV RNA cargo. However, from mammals to microbes, these assumptions do not seem to fall out of the data. In addition, miRNAs need to localize to the cytosol to be active but are likely to start in endosomes in most EV entry pathways. The mechanisms for their endosomal escape and the quantities of imported miRNAs required for their functions are not always considered. Without questioning the empirical evidence supporting EV-miRNA-mediated intercellular communication, we would like to shed light on the overlooked aspects of the exRNA biology that may bear important insights into how cells and organisms interact and sense one another.
Insights
Extracellular RNA (exRNA) research needs to reconsider assumptions about extracellular vesicles (EVs) and microRNAs (miRNAs) as primary carriers and cargo, respectively, for intercellular communication.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The field of extracellular RNA (exRNA) biology has expanded significantly.
- Current research often assumes extracellular vesicles (EVs) are the primary carriers of RNA between cells.
- MicroRNAs (miRNAs) are frequently presumed to be the main RNA cargo within EVs.
Purpose of the Study:
- To critically examine prevailing assumptions in exRNA research.
- To highlight overlooked aspects of exRNA biology, particularly concerning EV-miRNA interactions.
- To explore alternative mechanisms and considerations for intercellular RNA communication.
Main Methods:
- Review and critical analysis of existing data and assumptions in exRNA research.
- Examination of the biological requirements for miRNA activity, including cellular localization and endosomal escape.
- Consideration of the quantities of intercellularly transferred miRNAs necessary for biological function.
Main Results:
- Data from mammals to microbes challenge the assumption that EVs are the sole or main carriers of exRNAs.
- The role of miRNAs as the predominant EV RNA cargo is questioned.
- Potential mechanistic challenges for miRNA function, such as endosomal escape and required cellular concentrations, are highlighted.
Conclusions:
- The field of exRNA biology may benefit from questioning established paradigms regarding EV-miRNA communication.
- Further investigation into overlooked aspects of exRNA trafficking and function is warranted.
- A deeper understanding of exRNA biology can provide crucial insights into cellular and organismal interactions.
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