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
2025-07-17
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.