Journal Article

DZNE-2025-01030

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.

Madej, M. ; Ngoc, P. C. T. ; Muthukumar, S. ; Konturek-Cieśla, A. ; Tucciarone, S. ; Germanos, A. ; Ashworth, C. ; Kotarsky, K. ; Ghosh, S. ; Fan, Z. ; Fritz, H. ; Pascual-Gonzalez, I. ; Huerta, A. ; Guzzi, N. ; Colazzo, A. ; Beneventi, G. ; Lee, H.-m.DZNE* ; Cieśla, M. ; Douse, C. ; Kato, H. ; Swaminathan, V. ; Agace, W. W. ; Castellanos-Rubio, A. ; Salomoni, P.DZNE* ; Bryder, D. ; Bellodi, C.

2025
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.celrep.2025.115735

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.

Keyword(s): Animals (MeSH) ; Retroelements: genetics (MeSH) ; Inflammation: genetics (MeSH) ; Inflammation: pathology (MeSH) ; Inflammation: metabolism (MeSH) ; Mice (MeSH) ; RNA, Transfer: metabolism (MeSH) ; RNA, Transfer: genetics (MeSH) ; Mice, Knockout (MeSH) ; Humans (MeSH) ; Immunity, Innate (MeSH) ; Intramolecular Transferases: metabolism (MeSH) ; Intramolecular Transferases: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Hydro-Lyases: metabolism (MeSH) ; Hydro-Lyases: genetics (MeSH) ; Interferons: metabolism (MeSH) ; Signal Transduction (MeSH) ; Membrane Proteins: metabolism (MeSH) ; CP: Molecular biology ; PUS10 ; RNA-DNA hybrids ; cGAS-STING ; hematopoietic stem cell ; inflammation ; inflammatory bowel disease ; interferon ; pseudouridine ; tRNA-derived small RNAs ; transposable elements ; viral mimicry ; Retroelements ; RNA, Transfer ; pseudouridine synthases ; Intramolecular Transferases ; Hydro-Lyases ; Interferons ; Membrane Proteins

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Contributing Institute(s):

1. Nuclear Function in CNS Pathophysiology (AG Salomoni)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
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