{"doi":"10.1073/pnas.2319569121","title":"The tRNA <sup>Val</sup> half: A strong endogenous Toll-like receptor 7 ligand with a 5′-terminal universal sequence signature","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.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":419470,"datarank":0.5606504427425053,"base_score":3.7376696182833684,"endowment":3.7376696182833684,"self_citation_contribution":0.5606504427425053,"citation_network_contribution":0.0,"self_endowment_contribution":0.5606504427425053,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":749694,"name":"Takuya Kawamura","orcid":"0000-0002-0355-5699","position":1,"is_corresponding":false},{"id":210816,"name":"Yohei Kirino","orcid":"0000-0001-5232-4742","position":2,"is_corresponding":false},{"id":275148,"name":"Kamlesh Pawar","orcid":"0000-0002-9767-0152","position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:14.586331Z","pmid":"38683985","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}