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PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation

Madej, Magdalena LU ; Ngoc, Phuong Cao Thi LU orcid ; Muthukumar, Sowndarya LU ; Konturek-Cieśla, Anna ; Tucciarone, Silvia LU ; Germanos, Alexandre LU ; Ashworth, Christian LU ; Kotarsky, Knut LU ; Ghosh, Sudip LU and Fan, Zhimeng LU , et al. (2025) In Cell Reports 44(6).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Reports
volume
44
issue
6
article number
115735
publisher
Cell Press
external identifiers
  • scopus:105005368837
  • pmid:40402745
ISSN
2211-1247
DOI
10.1016/j.celrep.2025.115735
language
English
LU publication?
yes
additional info
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
id
95dd49f1-77aa-4012-9452-be901fa6e1f8
date added to LUP
2025-05-27 14:04:14
date last changed
2025-07-09 07:46:16
@article{95dd49f1-77aa-4012-9452-be901fa6e1f8,
  abstract     = {{<p>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.</p>}},
  author       = {{Madej, Magdalena and Ngoc, Phuong Cao Thi and Muthukumar, Sowndarya and Konturek-Cieśla, Anna and Tucciarone, Silvia and Germanos, Alexandre and Ashworth, Christian and Kotarsky, Knut and Ghosh, Sudip and Fan, Zhimeng and Fritz, Helena and Pascual-Gonzalez, Izei and Huerta, Alain and Guzzi, Nicola and Colazzo, Anita and Beneventi, Giulia and Lee, Hang-Mao and Cieśla, Maciej and Douse, Christopher and Kato, Hiroki and Swaminathan, Vinay and Agace, William W and Castellanos-Rubio, Ainara and Salomoni, Paolo and Bryder, David and Bellodi, Cristian}},
  issn         = {{2211-1247}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports}},
  title        = {{PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation}},
  url          = {{http://dx.doi.org/10.1016/j.celrep.2025.115735}},
  doi          = {{10.1016/j.celrep.2025.115735}},
  volume       = {{44}},
  year         = {{2025}},
}