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Berouti, M.* ; Wagner, M.* ; Greulich, W.* ; Piseddu, I.* ; Gärtig, J.* ; Hansbauer, L.* ; Müller-Hermes, C. ; Heiss, M.* ; Pichler, A.* ; Tölke, A.J.* ; Witte, G.* ; Hopfner, K.P.* ; Anz, D.* ; Sattler, M. ; Carell, T.* ; Hornung, V.*

Pseudouridine RNA avoids immune detection through impaired endolysosomal processing and TLR engagement.

Cell, DOI: 10.1016/j.cell.2025.05.032 (2025)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Recognition of exogenous RNA by Toll-like receptors (TLRs) is central to pathogen defense. Using two distinct binding pockets, TLR7 and TLR8 recognize RNA degradation products generated by endolysosomal nucleases. RNA modifications present in endogenous RNA prevent TLR activation; notably, pseudouridine-containing RNA lacks immunostimulatory activity. Indeed, this property has been critical to the successful implementation of mRNA technology for medical purposes. However, the molecular mechanism for this immune evasion has remained elusive. Here, we report that RNase T2 and PLD exonucleases do not adequately process pseudouridine-containing RNA to generate TLR-agonistic ligands. As a second safety mechanism, TLR8 neglects pseudouridine as a ligand for its first binding pocket and TLR7 neglects pseudouridine-containing RNA as a ligand for its second pocket. Interestingly, the medically used N1-methylpseudouridine also evades RNase T2, PLD3, and PLD4 processing but is able to directly activate TLR8. Taken together, our findings provide a molecular basis for self-avoidance by RNA-sensing TLRs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter N1-methylpseudouridine ; Pld3 ; Pld4 ; Rnase T2 ; Tlr7 ; Tlr8 ; Toll-like Receptors ; Endolysosomal Nucleases ; Immunostimulation ; Pseudouridine
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
DOI 10.1016/j.cell.2025.05.032
Scopus ID 105009265772
PubMed ID 40580950
Erfassungsdatum 2025-07-10
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