Membrane-derived microvesicles (MVs) include a range of extracellular vesicles, including exosomes, microparticles and shed MVs secreted by many cell types under both normal physiological and pathological conditions [1]. As intercellular communication tools, MVs have been reported to have roles in a wide range of cellular functions: immunological modulation, coagulation, and tumor progression, including angiogenesis and metastasis [2,3]. Additionally, they have been reported to serve as vehicles for transferring cargo (mRNA, miRNA, non-coding RNAs, proteins and oncogenes) between cells [4-8]. The mRNA content in MVs opens new research opportunities from cancer diagnostics to gene therapy applications [9-12]. Despite the intensive research in analyzing the RNA content of MVs, it remains unclear how RNAs are directed to MVs.
Mechanistically, cis-acting regulatory sequences and trans-acting proteins are considered as the main driving forces of mRNA localization within cells and have an important role in post-transcriptional regulation. Such sequences, also known as zip codes, are typically found in the 3′-untranslated regions (3′ UTRs) of mRNA transcripts and mediate binding of a ribonuclear protein complex to the mRNA which temporarily blocks its translation and mediates movement via the cytoskeleton to a cellular location where it releases the mRNA and translation commences [13,14].
In addition to zip codes, microRNAs (miRNAs) also have a critical role in post-transcriptional regulation of mRNAs. miRNAs are small, non-coding, single-stranded RNA molecules [˜21-23 nucleotides (nt) long] that regulate levels of gene expression in many organisms [15]. miRNAs mediate post-transcriptional regulation in three ways, by mRNA degradation, mRNA destabilization via deadenylation and translational repression [16]. In addition to negative regulation, miRNAs have also been reported to function in the activation of translation in some cases [17]. Although zip codes and miRNA target sequences are both found in the 3′UTRs of the mRNA transcripts, there has been no report of cooperation between these two regulatory mechanisms in mRNA fate.