课题组人员发现缺氧诱导的tDR，来源于tRNA-Asp-GTC的3’ 端（tRNA-Asp-GTC-3 ’ dr），激活肾细胞的自噬通量，而其沉默则阻断自噬通量。小鼠肾脏疾病模型的功能增益/功能丧失研究表明，tRNA-Asp-GTC-3 ’ dr具有显著的肾保护功能。从机制上说，tRNA-Asp-GTC-3 ’ dr组装了稳定的G-四联体结构，并隔离了假三烯嘧啶合成酶PUS7，阻止了组蛋白mRNAs的催化假三烯嘧啶化。由此产生的伪虹膜酰基化缺陷将组蛋白mRNAs定向到自噬体-溶酶体途径，引发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，提示临床相关性。其中，tRNA-Asp-GTC-3 ’ dr在调节RNA自噬中发挥作用，有助于维持肾细胞内稳态，防止肾损伤。
研究人员表示，转移RNA衍生的小RNA （tsRNAs或tDR）执行一系列细胞功能。
附：英文原文
Title: A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy
Author: Guoping Li, Lingfei Sun, Cuiyan Xin, Tian Hao, Prakash Kharel, Aidan C. Manning, Christopher L. OConnor, 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. GoddardIII, Todd M. Lowe, Patrick Pirrotte, Markus Bitzer, Pavel Ivanov, Joseph V. Bonventre, Saumya Das
Issue&Volume: 2025-07-17
Abstract: 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.
DOI: adp5384
Source: https://www.science.org/doi/10.1126/science.adp5384