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

Transfer RNA-derived small RNAs (tsRNAs, or tDRs) perform a range of cellular functions. Here, we showed that a hypoxia-induced tDR, derived from the 3' end of tRNA-Asp-GTC (tRNA-Asp-GTC-3'tDR), activated autophagic flux in kidney cells, while its silencing blocked autophagic flux. Functional gain/loss-of-function studies in murine kidney disease models demonstrated a significant reno-protective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 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.