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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-17 DOI:10.1126/science.adp5384

Guoping Li, Lingfei Sun, Cuiyan Xin, Tian Hao, 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, 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 Goddard, Todd M Lowe, Patrick Pirrotte, Markus Bitzer, Pavel Ivanov, Joseph V Bonventre, Saumya Das

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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.

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缺氧反应的trna衍生的小RNA通过RNA自噬赋予肾脏保护作用。

转移rna衍生的小rna （tsRNAs或tdr）执行一系列细胞功能。在这里，我们发现缺氧诱导的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 - tdr具有显著的肾保护功能。从机制上说，trna - asp - gtc -3 - tdr组装了稳定的g -四联体结构，并隔离了假尿嘧啶合成酶PUS7，阻止了组蛋白mrna的催化假尿嘧啶化。由此产生的假尿嘧啶化缺陷将组蛋白mrna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。因此，tRNA-Asp-GTC-3'tDR在调节RNA自噬中发挥作用，有助于维持肾细胞内稳态，保护肾脏免受损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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