Abstract
The exchange of extracellular vesicles (EV) between immune cells plays a role in various immune regulatory processes. EV are nano-sized lipid bilayer-enclosed structures that contain a multitude of proteins and small non-coding RNA molecules. Of the various RNA classes present in EV, miRNAs have been most intensively studied because of their known gene-regulatory functions. These miRNAs constitute only a minor part of all EV-enclosed RNA, whereas other 20–200 nt sized non-coding RNAs were shown to be abundantly present in EV. Several of these mid-sized RNAs perform basic functions in cells, but their function in EV remains elusive. One prominent class of mid-sized extracellular RNAs associated with EV are the Y-RNAs. This family of highly conserved non-coding RNAs was initially discovered as RNA component of circulating ribonucleoprotein autoantigens in serum from Systemic Lupus Erythematosus and Sjögren's Syndrome patients. Y-RNA has been implicated in cellular processes such as DNA replication and RNA quality control. In recent years, Y-RNA has been abundantly detected in EV from multiple different cell lines and biofluids, and also in murine and human retroviruses. Accumulating evidence suggests that EV-associated Y-RNA may be involved in a range of immune-related processes, including inflammation, immune suppression, and establishment of the tumor microenvironment. Moreover, changes in plasma levels of extracellular Y-RNA have been associated with various diseases. Recent studies have aimed to address the mechanisms underlying their release and function. We for example showed that the levels of EV-associated Y-RNA released by immune cells can be regulated by Toll-like receptor (TLR) signaling. Combined, these data have triggered increased interest in extracellular Y-RNAs. In this review, we provide an overview of studies reporting the occurrence of extracellular Y-RNAs, as well as signaling properties and immune-related functions attributed to these RNAs. We list RNA-binding proteins currently known to interact with Y-RNAs and evaluate their occurrence in EV. In parallel, we discuss technical challenges in assessing whether extracellular Y-RNAs are contained in ribonucleoprotein complexes or EV. By integrating the current knowledge on extracellular Y-RNA we further reflect on the biomarker potential of Y-RNA and their role in immune cell communication and immunopathology.
Highlights
Extracellular vesicles (EV) are 50–300 nm sized lipid bilayerenclosed vesicles containing proteins and nucleic acids [1], which are released by virtually all cells
Our laboratory recently showed that incorporation of Y-releasing their internal (RNA) in EV released by dendritic cells is regulated by immunogenic and tolerogenic stimuli imposed on these cells [16]
We have previously shown that, in addition to miRNA, the levels of YRNA and snoRNA in EV are regulated by exogenous stimuli imposed on the EV-producing immune cells [16]
Summary
Extracellular vesicles (EV) are 50–300 nm sized lipid bilayerenclosed vesicles containing proteins and nucleic acids [1], which are released by virtually all cells. The experimental approaches used to study miRNA transfer may serve as a basis to gain understanding of how other EV-associated RNA classes affect recipient cell behavior, but these RNAs likely exert their functions via mechanisms other than base-pairing with RNA targets. The highly conserved family of Y-RNAs interacts with, and regulates the localization and activity of various RNA-binding proteins involved in basic cell functions. Differences exist between studies that used different cell types or EV-purification methods, Y4 is most abundantly detected in the TABLE 1 | Overview of RNA sequencing studies reporting the presence of extracellular Y-RNA in in vitro cell cultures or in body fluids
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