The tRNAVal half: A strong endogenous Toll- like receptor 7 ligand with a 5′- terminal universal sequence signature
成果类型：
Article
署名作者：
Pawar, Kamlesh; Kawamura, Takuya; Kirino, Yohei
署名单位：
Thomas Jefferson University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-10473
DOI：
10.1073/pnas.2319569121
发表日期：
2024-05-07
关键词：
pattern-recognition receptors
single-stranded rna
tlr7
identification
activation
responses
micrornas
guanosine
viruses
origin
摘要：
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.