A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Guoping Li; Lingfei Sun; Cuiyan Xin; Tian Hao; Prakash Kharel; Aidan C Manning; Christopher L O'Connor; Henry Moore; Shuwen Lei; Priyanka Gokulnath; Xinyu Yang; Ritin Sharma; Krystine Garcia-Mansfield; Priyadarshini Pantham; Chunyang Xiao; Hanna Y Wang; Emeli Chatterjee; Seungbin Yim; Leo B Ren; Michail Spanos; Hua Zhu; Haobo Li; Ji Lei; James F Markmann; Louise C Laurent; John J Rossi; Oluwaseun Akeju; Quanhu Sheng; Ravi V Shah; William A Goddard; Todd M Lowe; Patrick Pirrotte; Markus Bitzer; Pavel Ivanov; Joseph V Bonventre; Saumya Das

doi:10.1126/science.adp5384

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A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

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Abstract

Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 7 (PUS7), preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

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Animals Autophagy Mice Humans Kidney RNA, Small Untranslated RNA, Messenger Cell Hypoxia Pseudouridine RNA, Transfer Mice, Inbred C57BL Male Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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Guoping Li, Lingfei Sun, Cuiyan Xin, Tian Hao, Prakash Kharel, Aidan C Manning, Christopher L O'Connor, Henry Moore, Shuwen Lei, Priyanka Gokulnath, Xinyu Yang, Ritin Sharma, Krystine Garcia-Mansfield, Priyadarshini Pantham, Chunyang Xiao, Hanna Y Wang, Emeli Chatterjee, Seungbin Yim, Leo B Ren, Michail Spanos, Hua Zhu, Haobo Li, Ji Lei, James F Markmann, Louise C Laurent, John J Rossi, Oluwaseun Akeju, Quanhu Sheng, Ravi V Shah, William A Goddard, Todd M Lowe, Patrick Pirrotte, Markus Bitzer, Pavel Ivanov, Joseph V Bonventre, Saumya Das. 2025-08-28. A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.. https://doi.org/10.1126/science.adp5384

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