TLR8 Is a Sensor of RNase T2 Degradation Products

Greulich, Wilhelm; Wagner, Mirko; Gaidt, Moritz M.; Stafford, Che; Cheng, Yiming; Linder, Andreas; Carell, Thomas und Hornung, Veit (27. November 2019): TLR8 Is a Sensor of RNase T2 Degradation Products. In: Cell, Bd. 179, Nr. 6: S. 1264-1275

Abstract

TLR8 is among the highest-expressed pattern-recognition receptors in the human myeloid compartment, yet its mode of action is poorly understood. TLR8 engages two distinct ligand binding sites to sense RNA degradation products, although it remains unclear how these ligands are formed in cellulo in the context of complex RNA molecule sensing. Here, we identified the lysosomal endoribonuclease RNase T2 as a non-redundant upstream component of TLR8-dependent RNA recognition. RNase T2 activity is required for rendering complex single-stranded, exogenous RNA molecules detectable for TLR8. This is due to RNase T2’s preferential cleavage of single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2′,3′-cyclophosphate-terminated oligoribonucleotides. Thus-generated molecules constitute agonistic ligands for the first and second binding pocket of TLR8. Together, these results establish the identity and origin of the RNA-derived molecular pattern sensed by TLR8.

• Dokumententyp: Zeitschriftenartikel
• EU Funded Grant Agreement Number: 741912
• EU-Projekte: Horizon 2020 > ERC Grants > ERC Advanced Grant > ERC Grant 741912: EPiR - The Chemical Basis of RNA Epigenetics
• Publikationsform: Postprint
• Keywords: innate immunity; toll-like receptor; pattern; recognition; TLR8; RNA; RNase T2; macrophage; monocyte
• Fakultät: Chemie und Pharmazie > Department Biochemie ; Chemie und Pharmazie > Department Chemie ; Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik IV (Endokrinologie, Nephrologie, weitere Sektionen)
• Fakultätsübergreifende Einrichtungen: Center for Integrated Protein Science Munich (CIPSM)
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• Bemerkung: This work was supported by grants from the European Research Council (ERC) (ERC-2016- ADG – project 741912 EPiR) ... Moreover, support was provided by grants from the ERC (ERC-2014-CoG – project 647858 GENESIS) ...
• Sprache: Englisch

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