Li Guoping, Sun Lingfei, Xin Cuiyan, Hao Tian, Kharel Prakash, Manning Aidan C, O'Connor Christopher L, Moore Henry, Lei Shuwen, Gokulnath Priyanka, Yang Xinyu, Sharma Ritin, Garcia-Mansfield Krystine, Pantham Priyadarshini, Xiao Chunyang, Wang Hanna Y, Chatterjee Emeli, Yim Seungbin, Ren Leo B, Spanos Michail, Zhu Hua, Li Haobo, Lei Ji, Markmann James F, Laurent Louise C, Rossi John J, Akeju Oluwaseun, Sheng Quanhu, Shah Ravi V, Goddard William A, Lowe Todd M, Pirrotte Patrick, Bitzer Markus, Ivanov Pavel, Bonventre Joseph V, Das Saumya
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Science. 2025 Aug 28;389(6763):eadp5384. doi: 10.1126/science.adp5384.
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.
转运RNA衍生的小RNA（tsRNAs或tDRs）具有一系列细胞功能。在此，我们表明tRNA-Asp-GTC-3'tDR是一种由tRNA-Asp-GTC的3'端衍生而来的缺氧诱导型tDR，它可激活肾细胞中的自噬流，而其沉默则会阻断自噬流。在小鼠肾脏疾病模型中进行的功能获得/功能丧失研究表明，tRNA-Asp-GTC-3'tDR具有显著的肾脏保护功能。从机制上讲，tRNA-Asp-GTC-3'tDR组装了稳定的G-四链体结构并隔离了假尿苷合酶7（PUS7），从而阻止了组蛋白mRNA的催化性假尿苷化。由此产生的假尿苷化缺陷将组蛋白mRNA导向自噬体-溶酶体途径，触发RNA自噬。这种tDR诱导的RNA自噬途径在小鼠和人类肾脏疾病期间被激活，提示其具有临床相关性。因此，tRNA-Asp-GTC-3'tDR在调节RNA自噬中发挥作用，这有助于维持肾细胞内的稳态并防止肾脏损伤。
