TY  - JOUR
AU  - Madej, Magdalena
AU  - Ngoc, Phuong Cao Thi
AU  - Muthukumar, Sowndarya
AU  - Konturek-Cieśla, Anna
AU  - Tucciarone, Silvia
AU  - Germanos, Alexandre
AU  - Ashworth, Christian
AU  - Kotarsky, Knut
AU  - Ghosh, Sudip
AU  - Fan, Zhimeng
AU  - Fritz, Helena
AU  - Pascual-Gonzalez, Izei
AU  - Huerta, Alain
AU  - Guzzi, Nicola
AU  - Colazzo, Anita
AU  - Beneventi, Giulia
AU  - Lee, Hang-mao
AU  - Cieśla, Maciej
AU  - Douse, Christopher
AU  - Kato, Hiroki
AU  - Swaminathan, Vinay
AU  - Agace, William W
AU  - Castellanos-Rubio, Ainara
AU  - Salomoni, Paolo
AU  - Bryder, David
AU  - Bellodi, Cristian
TI  - PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.
JO  - Cell reports
VL  - 44
IS  - 6
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DZNE-2025-01030
SP  - 115735
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Retroelements: genetics
KW  - Inflammation: genetics
KW  - Inflammation: pathology
KW  - Inflammation: metabolism
KW  - Mice
KW  - RNA, Transfer: metabolism
KW  - RNA, Transfer: genetics
KW  - Mice, Knockout
KW  - Humans
KW  - Immunity, Innate
KW  - Intramolecular Transferases: metabolism
KW  - Intramolecular Transferases: genetics
KW  - Mice, Inbred C57BL
KW  - Hydro-Lyases: metabolism
KW  - Hydro-Lyases: genetics
KW  - Interferons: metabolism
KW  - Signal Transduction
KW  - Membrane Proteins: metabolism
KW  - CP: Molecular biology (Other)
KW  - PUS10 (Other)
KW  - RNA-DNA hybrids (Other)
KW  - cGAS-STING (Other)
KW  - hematopoietic stem cell (Other)
KW  - inflammation (Other)
KW  - inflammatory bowel disease (Other)
KW  - interferon (Other)
KW  - pseudouridine (Other)
KW  - tRNA-derived small RNAs (Other)
KW  - transposable elements (Other)
KW  - viral mimicry (Other)
KW  - Retroelements (NLM Chemicals)
KW  - RNA, Transfer (NLM Chemicals)
KW  - pseudouridine synthases (NLM Chemicals)
KW  - Intramolecular Transferases (NLM Chemicals)
KW  - Hydro-Lyases (NLM Chemicals)
KW  - Interferons (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40402745
DO  - DOI:10.1016/j.celrep.2025.115735
UR  - https://pub.dzne.de/record/280948
ER  -