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

• 成果类型: Article
• 署名作者: [Anonymous]
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11540
• DOI: 10.1126/science.adp5384
• 发表日期: 2025-08-28
• 关键词: gene delivery; fragments; pseudouridylation; reveals; kidney

摘要

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.