PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation

PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation

Summary: Pseudouridine synthases (PUSs) catalyze the isomerization of uridine (U)-to-pseudouridine (Ψ) and have emerging roles in development and disease. How PUSs adapt gene expression under stress remains mostly unexplored. We identify an unconventional role for the Ψ “writer” PUS10 impacting intr...

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Main Authors: Magdalena Madej, Phuong Cao Thi Ngoc, Sowndarya Muthukumar, Anna Konturek-Cieśla, Silvia Tucciarone, Alexandre Germanos, Christian Ashworth, Knut Kotarsky, Sudip Ghosh, Zhimeng Fan, Helena Fritz, Izei Pascual-Gonzalez, Alain Huerta, Nicola Guzzi, Anita Colazzo, Giulia Beneventi, Hang-Mao Lee, Maciej Cieśla, Christopher Douse, Hiroki Kato, Vinay Swaminathan, William W. Agace, Ainara Castellanos-Rubio, Paolo Salomoni, David Bryder, Cristian Bellodi
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:Cell Reports
Subjects:
CP: Molecular biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725005066
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Summary:Summary: Pseudouridine synthases (PUSs) catalyze the isomerization of uridine (U)-to-pseudouridine (Ψ) and have emerging roles in development and disease. How PUSs adapt gene expression under stress remains mostly unexplored. We identify an unconventional role for the Ψ “writer” PUS10 impacting intracellular innate immunity. Using Pus10 knockout mice, we uncover cell-intrinsic upregulation of interferon (IFN) signaling, conferring resistance to inflammation in vivo. Pus10 loss alters tRNA-derived small RNAs (tdRs) abundance, perturbing translation and endogenous retroelements expression. These alterations promote proinflammatory RNA-DNA hybrids accumulation, potentially activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING). Supplementation with selected tdR pools partly rescues these effects through interactions with RNA processing factors that modulate immune responses, revealing a regulatory circuit that counteracts cell-intrinsic inflammation. By extension, we define a PUS10-specific molecular fingerprint linking its dysregulation to human autoimmune disorders, including inflammatory bowel diseases. Collectively, these findings establish PUS10 as a viral mimicry modulator, with broad implications for innate immune homeostasis and autoimmunity.
ISSN:2211-1247

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