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@ARTICLE{Madej:280948,
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},
title = {{PUS}10-induced t{RNA} fragmentation impacts
retrotransposon-driven inflammation.},
journal = {Cell reports},
volume = {44},
number = {6},
issn = {2211-1247},
address = {Maryland Heights, MO},
publisher = {Cell Press},
reportid = {DZNE-2025-01030},
pages = {115735},
year = {2025},
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
(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.},
keywords = {Animals / Retroelements: genetics / Inflammation: genetics
/ Inflammation: pathology / Inflammation: metabolism / Mice
/ RNA, Transfer: metabolism / RNA, Transfer: genetics /
Mice, Knockout / Humans / Immunity, Innate / Intramolecular
Transferases: metabolism / Intramolecular Transferases:
genetics / Mice, Inbred C57BL / Hydro-Lyases: metabolism /
Hydro-Lyases: genetics / Interferons: metabolism / Signal
Transduction / Membrane Proteins: metabolism / CP: Molecular
biology (Other) / PUS10 (Other) / RNA-DNA hybrids (Other) /
cGAS-STING (Other) / hematopoietic stem cell (Other) /
inflammation (Other) / inflammatory bowel disease (Other) /
interferon (Other) / pseudouridine (Other) / tRNA-derived
small RNAs (Other) / transposable elements (Other) / viral
mimicry (Other) / Retroelements (NLM Chemicals) / RNA,
Transfer (NLM Chemicals) / pseudouridine synthases (NLM
Chemicals) / Intramolecular Transferases (NLM Chemicals) /
Hydro-Lyases (NLM Chemicals) / Interferons (NLM Chemicals) /
Membrane Proteins (NLM Chemicals)},
cin = {AG Salomoni},
ddc = {610},
cid = {I:(DE-2719)1013032},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40402745},
doi = {10.1016/j.celrep.2025.115735},
url = {https://pub.dzne.de/record/280948},
}