A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy
Guoping Li, Lingfei Sun, Cuiyan Xin, Hao Tian, 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, He Wang, Emeli Chatterjee, S 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, П. Л. Иванов, Joseph V. Bonventre, Saumya Das
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.