PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation
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.
Authors
- Giulia Beneventi (ORCID: https://orcid.org/0000-0002-8287-4515)
- Christopher Douse
- William W. Agace (ORCID: https://orcid.org/0000-0003-3823-5772)
- H Fritz (ORCID: https://orcid.org/0000-0001-7416-4962)
- Anna Konturek-Cieśla (ORCID: https://orcid.org/0000-0003-1746-930X)
- Nicola Guzzi (ORCID: https://orcid.org/0000-0002-3898-8064)
- Ainara Castellanos‐Rubio (ORCID: https://orcid.org/0000-0003-3192-9544)
- Sudip Ghosh (ORCID: https://orcid.org/0000-0001-8277-0639)
- Cristian Bellodi (ORCID: https://orcid.org/0000-0001-8047-5329)
- Hiroki Kato (ORCID: https://orcid.org/0000-0002-4021-3356)
- Vinay Swaminathan (ORCID: https://orcid.org/0000-0002-9946-810X)
- Hang‐Mao Lee (ORCID: https://orcid.org/0000-0002-3838-0294)
- David Bryder (ORCID: https://orcid.org/0000-0002-8761-4237)
- Phuong Cao Thi Ngoc (ORCID: https://orcid.org/0000-0002-3059-9179)
- Alaín Huerta (ORCID: https://orcid.org/0000-0002-8795-1428)
- Paolo Salomoni
- Magdalena Madej (ORCID: https://orcid.org/0000-0003-3821-3514)
- Sowndarya Muthukumar (ORCID: https://orcid.org/0000-0002-9110-722X)
- Alexandre A. Germanos (ORCID: https://orcid.org/0000-0003-4677-1313)
- Christian Ashworth (ORCID: https://orcid.org/0000-0002-4206-9490)
- Knut Kotarsky (ORCID: https://orcid.org/0000-0003-3785-0327)
- Zhimeng Fan (ORCID: https://orcid.org/0009-0009-6192-7874)
- Maciej Cieśla (ORCID: https://orcid.org/0000-0002-8460-1991)
- Silvia Tucciarone
- Izei Pascual-González (ORCID: https://orcid.org/0009-0006-4665-0828)
- Anita Colazzo
Institutions
- University of Copenhagen (DK)
- University of Bonn (DE)
- University of the Basque Country (ES)
- Lund University (SE)
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- Polish Institute of International Affairs (PL)
- BioCruces Health research Institute (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Hospital de Galdakao (ES)
- LEO Foundation (DK)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1016/j.celrep.2025.115735
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University College London
- Cancerfonden
- Vetenskapsrådet
- Ministerio de Ciencia e Innovación
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Deutsche Krebshilfe
- Barncancerfonden