Infection-induced 5′-half molecules of tRNAHisGUG activate Toll-like receptor 7

• DOI: 10.1371/journal.pbio.3000982
• Publication Date: 2020-12-17T19:17:01Z
• Authors: Kamlesh Pawar; Megumi Shigematsu; Soroush Sharbati; Yohei Kirino
• Keywords: 0301 basic medicine; 570; QH301-705.5; THP-1 Cells; Endosomes; exosomes; RNA, Transfer, His; pattern-recognition; NF-κB; noncoding RNA; Extracellular Vesicles; 03 medical and health sciences; RNA, Transfer; Medicine and Health Sciences; Humans; Biology (General); Macrophages; 500; 500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie; Immunity, Innate; macrophages; 3. Good health; Gene Expression Regulation; Toll-Like Receptor 7; antiviral responses; transfer-RNA fragments; identification; Research Article

Toll-like receptors (TLRs) play a crucial role in the innate immune response. Although endosomal TLR7 recognizes single-stranded RNAs, their endogenous RNA ligands have not been fully explored. Here, we report 5′-tRNA half molecules as abundant activators of TLR7. Mycobacterial infection and accompanying surface TLR activation up-regulate the expression of 5′-tRNA half molecules in human monocyte-derived macrophages (HMDMs). The abundant accumulation of 5′-tRNA halves also occur in HMDM-secreted extracellular vehicles (EVs); the abundance of EV-5′-tRNAHisGUGhalf molecules is >200-fold higher than that of the most abundant EV-microRNA (miRNA). Sequence identification of the 5′-tRNA halves using cP-RNA-seq revealed abundant and selective packaging of specific 5′-tRNA half species into EVs. The EV-5′-tRNAHisGUGhalf was experimentally demonstrated to be delivered into endosomes in recipient cells and to activate endosomal TLR7. Up-regulation of the 5′-tRNA half molecules was also observed in the plasma of patients infected withMycobacterium tuberculosis. These results unveil a novel tRNA-engaged pathway in the innate immune response and assign the role of “immune activators” to 5′-tRNA half molecules.