Toward an Understanding of Extracellular tRNA Biology.

Adrian Gabriel Torres,Eulàlia Martí

doi:10.3389/fmolb.2021.662620

Abstract

Extracellular RNAs (exRNAs) including abundant full length tRNAs and tRNA fragments (tRFs) have recently garnered attention as a promising source of biomarkers and a novel mediator in cell-to-cell communication in eukaryotes. Depending on the physiological state of cells, tRNAs/tRFs are released to the extracellular space either contained in extracellular vesicles (EVs) or free, through a mechanism that is largely unknown. In this perspective article, we propose that extracellular tRNAs (ex-tRNAs) and/or extracellular tRFs (ex-tRFs) are relevant paracrine signaling molecules whose activity depends on the mechanisms of release by source cells and capture by recipient cells. We speculate on how ex-tRNA/ex-tRFs orchestrate the effects in target cells, depending on the type of sequence and the mechanisms of uptake. We further propose that tRNA modifications may be playing important roles in ex-tRNA biology.

Highlights

All cells are able to release RNA to the extracellular space [extracellular RNAs] either free, encapsulated in extracellular vesicles (EVs) (Fabbiano et al, 2020; Zietzer et al, 2020), or forming part of complexes with proteins such as Argonaute 2 (Ago2) (Arroyo et al, 2011; Turchinovich et al, 2011) and high-density lipoprotein (HDL) particles (Vickers et al, 2011)
Studies on the biological significance of Extracellular RNAs (exRNAs) have largely focused on EVs content, which is protected from extracellular RNases
Specific types of tRNA fragments (tRFs) cannot be envisioned as by-products of tRNA turnover and mounting evidence reveal them as a novel class of sRNAs that regulate gene expression through multiple mechanisms

Summary

INTRODUCTION

All cells are able to release RNA to the extracellular space [extracellular RNAs (exRNA)] either free, encapsulated in extracellular vesicles (EVs) (Fabbiano et al, 2020; Zietzer et al, 2020), or forming part of complexes with proteins such as Argonaute 2 (Ago2) (Arroyo et al, 2011; Turchinovich et al, 2011) and high-density lipoprotein (HDL) particles (Vickers et al, 2011). We reason that tRNA/tRF release is a complex phenomenon, involving cell dependent passive and/or selective RNA sorting in different extracellular compartments, and likewise, that the possible mechanisms of capture and activity of these species in recipient cells may be cell type-specific and depend on the nature of the ex-tRNA/ex-tRF sequences. Non-vesicular exRNA transport into target cells has been shown for miRNAs associated with HDL, depending on a specific receptor (scavenger receptor class B type 1) (Vickers et al, 2011) This opens the likely possibility that tRNAs/tRFs complexed with HDL, which are by far more abundant than miRNAs (Tosar et al, 2020), analogously enter target cells. TRNA modifications may at least be important for ex-tRNA/ex-tRF function within recipient cells

DISCUSSION

DATA AVAILABILITY STATEMENT