Post-transcriptional modifications on tRNA fragments confer functional changes to high-density lipoproteins in atherosclerosis

Semler, E. M.; Michell, D. L.; Kingsley, P. J.; Massick, C.; Ramirez, M. A.; Castleberry, M. A.; Doran, A. C.; Carr, J. J.; Marnett, L. J.; Sheng, Q.; Linton, M. F.; Vickers, K. C.

doi:10.1101/2024.12.19.628772

bioRxiv · 10.1101/2024.12.19.628772

Post-transcriptional modifications on tRNA fragments confer functional changes to high-density lipoproteins in atherosclerosis

Semler, E. M.·Michell, D. L.·Kingsley, P. J.·Massick, C.·Ramirez, M. A.·Castleberry, M. A.·Doran, A. C.·Carr, J. J.·Marnett, L. J.·Sheng, Q.·Linton, M. F.·Vickers, K. C.

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Abstract

Epitranscriptomic modifications on RNA play critical roles in stability, processing, and function, partly by influencing interactions with RNA-binding proteins and receptors. The role of post-transcriptional RNA modifications on cell-free non-coding small RNA (sRNA) remains poorly understood in disease contexts. High-density lipoproteins (HDL), which transport sRNAs, can lose their beneficial properties in atherosclerosis cardiovascular disease (ASCVD). We hypothesize that changes to regulatory modifications on HDL-sRNAs contribute to this dysfunction. To assess changes in HDL-sRNA modification status, HDL-derived RNA from healthy subjects and those with atherosclerotic lesion development were analyzed using LC-MS/MS and AlkB-facilitated RNA (de)Methylation Sequencing. ASVD-HDL showed an enrichment in modified nucleosides including m1A tRNA-derived sRNAs (tDRs), particularly tDR-ArgACG-1. Functional studies revealed that ASCVD-HDL induced cell adhesion genes, including TMEM123, in primary macrophages. Recombinant HDL loaded with m1A-tDR-ArgACG-1 induced immune signaling, and similarly upregulated TMEM123. These findings suggest HDL-delivered-m1A-tDR-ArgACG-1 act on adhesion genes and immune pathways, promoting macrophage activation.

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Semler, E. M., Michell, D. L., Kingsley, P. J., Massick, C., Ramirez, M. A., Castleberry, M. A., Doran, A. C., Carr, J. J., Marnett, L. J., Sheng, Q., Linton, M. F., Vickers, K. C.. 2024-12-20. Post-transcriptional modifications on tRNA fragments confer functional changes to high-density lipoproteins in atherosclerosis. https://doi.org/10.1101/2024.12.19.628772

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