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

Guoping Li^{1

2}, Lingfei Sun¹, Cuiyan Xin³, Tian Hao², Prakash Kharel⁴, Aidan C Manning⁵, Christopher L O'Connor⁶, Henry Moore⁵, Shuwen Lei⁷, Priyanka Gokulnath¹, Xinyu Yang⁸, Ritin Sharma⁹, Krystine Garcia-Mansfield⁹, Priyadarshini Pantham¹⁰, Chunyang Xiao¹, Hanna Y Wang¹, Emeli Chatterjee¹, Seungbin Yim³, Leo B Ren³, Michail Spanos¹, Hua Zhu¹¹, Haobo Li², Ji Lei¹², James F Markmann¹², Louise C Laurent¹⁰, John J Rossi¹³, Oluwaseun Akeju², Quanhu Sheng¹⁴, Ravi V Shah¹⁵, William A Goddard 3rd⁷, Todd M Lowe⁵, Patrick Pirrotte⁹, Markus Bitzer^{6

16}, Pavel Ivanov⁴, Joseph V Bonventre³, Saumya Das¹

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Biomolecular Engineering, Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
⁶ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁷ Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, USA.
⁸ Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
⁹ Early Detection and Prevention Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
¹⁰ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
¹¹ Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹² Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
¹³ RNA Biology and Therapeutics, Beckmann Research Institute, City of Hope, Duarte, CA, USA.
¹⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁵ Vanderbilt Translational and Clinical Research Center, Cardiology Division, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.

PMID: 40674449
DOI: 10.1126/science.adp5384

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

Guoping Li et al. Science. 2025.

. 2025 Aug 28;389(6763):eadp5384.

doi: 10.1126/science.adp5384. Epub 2025 Aug 28.

Authors

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Biomolecular Engineering, Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
⁶ Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA.
⁷ Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, USA.
⁸ Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
⁹ Early Detection and Prevention Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
¹⁰ Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
¹¹ Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹² Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
¹³ RNA Biology and Therapeutics, Beckmann Research Institute, City of Hope, Duarte, CA, USA.
¹⁴ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁵ Vanderbilt Translational and Clinical Research Center, Cardiology Division, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.

PMID: 40674449
DOI: 10.1126/science.adp5384

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.

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

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

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Abstract

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