%0 Journal Article
%A Madej, Magdalena
%A Ngoc, Phuong Cao Thi
%A Muthukumar, Sowndarya
%A Konturek-Cieśla, Anna
%A Tucciarone, Silvia
%A Germanos, Alexandre
%A Ashworth, Christian
%A Kotarsky, Knut
%A Ghosh, Sudip
%A Fan, Zhimeng
%A Fritz, Helena
%A Pascual-Gonzalez, Izei
%A Huerta, Alain
%A Guzzi, Nicola
%A Colazzo, Anita
%A Beneventi, Giulia
%A Lee, Hang-mao
%A Cieśla, Maciej
%A Douse, Christopher
%A Kato, Hiroki
%A Swaminathan, Vinay
%A Agace, William W
%A Castellanos-Rubio, Ainara
%A Salomoni, Paolo
%A Bryder, David
%A Bellodi, Cristian
%T PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.
%J Cell reports
%V 44
%N 6
%@ 2211-1247
%C Maryland Heights, MO
%I Cell Press
%M DZNE-2025-01030
%P 115735
%D 2025
%X 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.
%K Animals
%K Retroelements: genetics
%K Inflammation: genetics
%K Inflammation: pathology
%K Inflammation: metabolism
%K Mice
%K RNA, Transfer: metabolism
%K RNA, Transfer: genetics
%K Mice, Knockout
%K Humans
%K Immunity, Innate
%K Intramolecular Transferases: metabolism
%K Intramolecular Transferases: genetics
%K Mice, Inbred C57BL
%K Hydro-Lyases: metabolism
%K Hydro-Lyases: genetics
%K Interferons: metabolism
%K Signal Transduction
%K Membrane Proteins: metabolism
%K CP: Molecular biology (Other)
%K PUS10 (Other)
%K RNA-DNA hybrids (Other)
%K cGAS-STING (Other)
%K hematopoietic stem cell (Other)
%K inflammation (Other)
%K inflammatory bowel disease (Other)
%K interferon (Other)
%K pseudouridine (Other)
%K tRNA-derived small RNAs (Other)
%K transposable elements (Other)
%K viral mimicry (Other)
%K Retroelements (NLM Chemicals)
%K RNA, Transfer (NLM Chemicals)
%K pseudouridine synthases (NLM Chemicals)
%K Intramolecular Transferases (NLM Chemicals)
%K Hydro-Lyases (NLM Chemicals)
%K Interferons (NLM Chemicals)
%K Membrane Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40402745
%R 10.1016/j.celrep.2025.115735
%U https://pub.dzne.de/record/280948