tRNA-derived small RNAs in disease immunity

Abstract

Recently, members of a unique species of non-coding RNA, known as transfer RNA-derived small RNAs (tsRNAs) have been reported to serve multiple molecular functions, including in cells that mediate immunity. Because of their low molecular weights, tsRNAs were previously difficult to detect and were thus overlooked, until now. In this review, we delve into the biogenesis of tsRNAs and their diverse biological functions, ranging from transcriptional regulation to modulation of mRNA translation. We highlight the current evidence demonstrating their involvement in the immune response, as well as how tsRNAs modulate immunity to influence tumor growth and spread, autoimmune disease pathology and infection by pathogens. We surmise that tsRNAs are likely informative as diagnostic markers of cellular homeostasis and disease, and that therapeutic targeting of tsRNAs could be beneficial for a range of human diseases. Improved knowledge on the functions for tsRNAs in the mammalian immune system will enable us to leverage tsRNAs for their effective clinical use as treatments for human health challenges.

Keywords: adaptive immunity; autoimmune diseases; biogenesis; non-coding RNA; tRNA-derived small RNA; tumor immunology.

Figure 1

Structure, classification and function of tRNA-derived small RNA (tsRNA). (A) tRNA structure: The tRNA mocular consists of four arms (acceptor arm, D arm, TΨC arm and anticodon arm), three loops (D loop, TΨC loop and anticodon loop) and a variable loop structure. The L-shaped tertiary structure model of tRNA is depicted in the lower right corner. (B) Classification and Biogenesisof tsRNA: tsRNA is primarily generated by specific nucleases (such as ANG, Dicer, SLFN13, RNase 1, RNase P, RNase Z, RNase T2, RNaseA, RNase L, etc.) that cleave mature tRNAs or during the processing of tRNA precursors. (C) Function of tsRNA: tsRNA participates in the regulation of numerous of biological processes, including epigenetic alterations, mRNA modifications, gene sciencing, RNA splicing, translational regulation and protein transport. For example, the 3'tRF-Val directly binds to the chaperone molecule EEF1A1, an interaction that does not affect the levels of EEF1A1 mRNA and protein but mediates its transport to the nucleus. This figure was created with BioRender.com.

Figure 2

Regulation of immune cell function by tsRNA. (A) In innate immunity, activated human monocyte-derived macrophages secrete extracellular vesicles (EVs) containing tsRNA, particularly EV-5'-tRNA-His-GUG half molecules, to activate the immune response. The 5'-tRNA-Val-CAC/AAC half-molecule effectively targets and eliminates intracellular pathogens by activating TLR7. (B) In adaptive immunity, T cell activation triggers the formation of multivesicular body (MVB) and the release of a specific set of tRFs via EVs derived from the 5' end and 3' inner region of trRNA without variable loops. This figure was created with BioRender.com.

Figure 3

tsRNA in tumor immunology. tsRNA within tumor cells contribute to immune evasion by enhancing the expression of PD-L1. Specific tsRNA species, including 5a_tRF-Cys-GCA, 3P_tRNA-Ser-GCT-6-1, 3P_tRNA-Thr-CGT-4-1, 3P_tRNA-Arg-TCT-4-1, and 5P_tRNA-Trp-CCA-3-3, have been identified to play a role in this process. However, the precise molecular mechanisms remain unclear. Additionally, tsRNA can recruit immunosuppressive macrophagesand myeloid-derived suppressor cells by modulating the interferon pathway, as exemplified by 5'-tRNA fragments. They also contribute to the formation of an immunosuppressive microenvironment by secreting exosomes containing tsRNAs, such as tRF-Glu-CTC-0005. Furthermore, tsRNAs can impede the effectiveness of immunotherapy by inhibiting apoptosis. For instance, tRF-3024b reduces tumor cell apoptosis by promoting BCL-2 expression, thereby inhibiting the therapeutic effects of immune checkpoint inhibitors. This figure was created with BioRender.com.

Figure 4

tsRNA's involvement in diverse immune-related diseases. tsRNA plays a role in various immune-related conditions, including different types of cancer such as bladder cancer, lung cancer, braest cancer, esophageal squamous cell carcinoma and pancreatic cancer. It is also implicated in autoimmune diseases like systemic lupus erythematosus and and sarcoidosis. Additionally, tsRNA is associated with bacterial and viral infections, including respiratory syncytial, SARS-Cov-2 and bovine leukemia virus. Other conditions where tsRNA is involved encompass hypertrophic scars, intrauterin growth restriction, diabetes, ischemia-reperfusion injury, muscle injury and fibrous dysplasia. This figure was created with BioRender.com.