The tRNAVal Half: A Strong Endogenous Toll-Like Receptor 7 Ligand with a 5′-Terminal Universal Sequence Signature

Authors

Kamlesh Ganesh Pawar, Thomas Jefferson UniversityFollow
Takuya Kawamura, Thomas Jefferson UniversityFollow
Yohei Kirino, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-7-2024

Comments

This article is the author's final published version in Proceedings of the National Academy of Sciences of the United States of America, Volume 121, Issue 19, May 2024, Pages e2319569121.

The published version is available at https://doi.org/10.1073/pnas.2319569121.

Copyright © 2024 the Author(s).

Abstract

Toll-like receptors (TLRs) are crucial components of the innate immune system. Endosomal TLR7 recognizes single-stranded RNAs, yet its endogenous ssRNA ligands are not fully understood. We previously showed that extracellular (ex-) 5'-half molecules of tRNA^HisGUG (the 5'-tRNA^HisGUG half) in extracellular vesicles (EVs) of human macrophages activate TLR7 when delivered into endosomes of recipient macrophages. Here, we fully explored immunostimulatory ex-5'-tRNA half molecules and identified the 5'-tRNA^ValCAC/AAC half, the most abundant tRNA-derived RNA in macrophage EVs, as another 5'-tRNA half molecule with strong TLR7 activation capacity. Levels of the ex-5'-tRNA^ValCAC/AAC half were highly up-regulated in macrophage EVs upon exposure to lipopolysaccharide and in the plasma of patients infected with Mycobacterium tuberculosis. The 5'-tRNA^ValCAC/AAC half-mediated activation of TLR7 effectively eradicated bacteria infected in macrophages. Mutation analyses of the 5'-tRNA^ValCAC/AAC half identified the terminal GUUU sequence as a determinant for TLR7 activation. We confirmed that GUUU is the optimal ratio of guanosine and uridine for TLR7 activation; microRNAs or other RNAs with the terminal GUUU motif can indeed stimulate TLR7, establishing the motif as a universal signature for TLR7 activation. These results advance our understanding of endogenous ssRNA ligands of TLR7 and offer insights into diverse TLR7-involved pathologies and their therapeutic strategies.

Recommended Citation

Pawar, Kamlesh Ganesh; Kawamura, Takuya; and Kirino, Yohei, "The tRNAVal Half: A Strong Endogenous Toll-Like Receptor 7 Ligand with a 5′-Terminal Universal Sequence Signature" (2024). Computational Medicine Center Faculty Papers. Paper 54.
https://jdc.jefferson.edu/tjucompmedctrfp/54

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

PubMed ID

38683985

Language

English