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

• 成果类型: Article
• 署名作者: 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., III; Lowe, Todd M.; Pirrotte, Patrick; Bitzer, Markus; Ivanov, Pavel; Bonventre, Joseph V.; Das, Saumya
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of California System; University of California Santa Cruz; University of Michigan System; University of Michigan; California Institute of Technology; Beijing University of Chinese Medicine; Translational Genomics Research Institute; University of California System; University of California San Diego; University System of Ohio; Ohio State University; University of Pennsylvania; Pennsylvania Medicine; City of Hope; Vanderbilt University; Vanderbilt University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Ann Arbor Healthcare System
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adp5384
• 发表日期: 2025-08-28
• 页码: eadp5384
• 关键词: gene delivery; fragments; pseudouridylation; reveals; kidney

摘要

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.