Regulatory RNAs: A Universal Language for Inter-Domain Communication

Abstract

In eukaryotes, microRNAs (miRNAs) have roles in development, homeostasis, disease and the immune response. Recent work has shown that plant and mammalian miRNAs also mediate cross-kingdom and cross-domain communications. However, these studies remain controversial and are lacking critical mechanistic explanations. Bacteria do not produce miRNAs themselves, and therefore it is unclear how these eukaryotic RNA molecules could function in the bacterial recipient. In this review, we compare and contrast the biogenesis and functions of regulatory RNAs in eukaryotes and bacteria. As a result, we discovered several conserved features and homologous components in these distinct pathways. These findings enabled us to propose novel mechanisms to explain how eukaryotic miRNAs could function in bacteria. Further understanding in this area is necessary to validate the findings of existing studies and could facilitate the use of miRNAs as novel tools for the directed remodelling of the human microbiota.

Keywords: RNA; communication; extracellular vesicles; miRNA; microbiota.

Figure 1

Biogenesis and functions of (A) miRNAs in eukaryotes and (B) trans-asRNAs in bacteria. (A) Eukaryotic miRNAs are transcribed in the nucleus into a pre-cursor primary-miRNA (pri-miRNA) transcript. The pri-miRNA is cleaved by Drosha (black scissors) to form a shorter hairpin, the pre-miRNA. The pre-miRNA is exported from the nucleus by exportin-5 in conjunction with ran-GTP. In the cytoplasm, the pre-miRNA is cleaved further by Dicer (red scissors) to form a miRNA duplex. One strand from the miRNA duplex is preferentially loaded onto Argonaute (AGO) forming the RNA-induced Silencing Complex (RISC). The miRNA of the RISC complex facilitates binding to the target mRNA (requiring only partial complementarity). Catalytically active AGOs (AGO2 in humans) can cleave and degrade the mRNA target. The RISC complex can also inhibit ribosomal translation of mRNAs. Exocytosis of miRNAs in Extracellular Vesicles (EVs) has been shown in eukaryotes [14]. It is not yet known whether the miRNA could be loaded onto AGO prior to exocytosis. (B) Newly transcribed bacterial trans-asRNAs can be stabilised by Hfq. Hfq can also facilitate binding between the trans-asRNA and the mRNA target [29,30]. In Gram-negative bacteria, Hfq can facilitate binding of the trans-asRNA and mRNA to RNase E which degrades both the asRNA and mRNA [31]. It is unclear whether RNase E can be exported from bacteria, but it does possess a domain capable of binding the membrane of phospholipid vesicles in vitro [32]. Bacteria have been shown to export microRNA-size RNA (msRNA) and trans-asRNAs in EVs [33,34,35]. Hfq can also be exported from bacteria in EVs [36] (Created with BioRender.com).

Figure 2

RNA-mediated communications between the mammalian host and the bacteria of the gastrointestinal microbiota. (A) The bacteria of the mammalian intestinal microbiota can indirectly alter the host miRNA profile through the production of metabolites and activation of Toll-like Receptors (TLRs). It is known that bacteria can produce microRNA-size RNAs (msRNAs) in Extracellular Vesicles (EVs) that can integrate into host miRNA pathways [47]. Other RNAs such as trans-asRNAs could be exported in vesicles and could similarly integrate into host pathways. It is also possible that asRNAs could be exported along with their effectors in EVs (such as Hfq and RNase E) and could directly influence host gene expression. EV-independent export of asRNAs could be mediated by Hfq, as Hfq can create holes in the bacterial cell membrane [79]. (B) Plant exosome-like nanoparticles (ELNs) from diet and EVs from intestinal epithelial cells containing miRNAs can enter members of the microbiota and influence bacterial gene expression and growth [14,16]. These miRNAs could be exported with effectors such as Argonaute (AGO) to directly alter bacterial gene expression. Alternatively, eukaryotic miRNAs could become functional upon integration into existing bacterial asRNA regulatory pathways (Created with BioRender.com).