Extracellular vesicles-associated tRNA-derived fragments (tRFs): biogenesis, biological functions, and their role as potential biomarkers in human diseases

Abstract

Traditionally, transfer RNAs (tRNAs) specifically decoded messenger RNA (mRNA) and participated in protein translation. tRNA-derived fragments (tRFs), also known as tRNA-derived small RNAs (tsRNAs), are generated by the specific cleavage of pre- and mature tRNAs and are a class of newly defined functional small non-coding RNAs (sncRNAs). Following the different cleavage positions of precursor or mature tRNA, tRFs are classified into seven types, 5'-tRNA half, 3'-tRNA half, tRF-1, 5'U-tRF, 3'-tRF, 5'-tRF, and i-tRF. It has been demonstrated that tRFs have a diverse range of biological functions in cellular processes, which include inhibiting protein translation, modulating stress response, regulating gene expression, and involvement in cell cycles and epigenetic inheritance. Emerging evidences have indicated that tRFs in extracellular vesicles (EVs) seem to act as regulatory molecules in various cellular processes and play essential roles in cell-to-cell communication. Furthermore, the dysregulation of EV-associated tRFs has been associated with the occurrence and progression of a variety of cancers and they can serve as novel potential biomarkers for cancer diagnosis. In this review, the biogenesis and classification of tRFs are summarized, and the biological functions of EV-associated tRFs and their roles as potential biomarkers in human diseases are discussed.

Keywords: Biological functions; Biomarker; Cancer; Extracellular vesicles (EVs); tRNA-derived fragments (tRFs).

Fig. 1

Classification of tRNA-derived fragments (tRFs). tRFs can be divided into 7 subtypes, 5′-tRNA half, 3′-tRNA half, tRF-1, 5′U-tRF, 3′-tRF, 5′-tRF, and i-tRF. tRNA half can be categorized into 2 types, 5′-tRNA half and 3′-tRNA half. They are cleaved by angiogenin (ANG) at the anticodon loop. tRF-1 is derived from precursor tRNAs digested by RNase Z or ELAC2. 5′U-tRF comes from 5′ leader of pre-tRNAs. 3′-tRF and 5′-tRF originate from mature tRNAs using ANG, Dicer, or other RNases. i‐tRF is from the internal region of mature tRNAs by ANG and Rny1

Fig. 2

The regulation of epigenetic inheritance by 5′-tRNA halves. Epididymosomes (a type of EVs) delivered tRFs to mature sperm. 5′-tRNA halves were discovered in a paternal mouse model with high-fat diet (HFD). Injection of these tRFs generated diet-induced metabolic disorders in F1 offspring. ND, normal diet

Fig. 3

The regulation of immune activation by 5′-tRFs. T cells release 5′-tRFs into extracellular vesicles (EVs) via the multivesicular body (MVB). Immune activation signal promotion of MVB formation and the secretion of specific tRF-enriched EVs. These 5′-tRFs repress both the activation of T cells and cytokine production within T cells