2. Academic Validation
  3. TLR8 Is a Sensor of RNase T2 Degradation Products

TLR8 Is a Sensor of RNase T2 Degradation Products

  • Cell. 2019 Nov 27;179(6):1264-1275.e13. doi: 10.1016/j.cell.2019.11.001.
Wilhelm Greulich 1,  Mirko Wagner 2,  Moritz M Gaidt 3,  Che Stafford 1,  Yiming Cheng 1,  Andreas Linder 4,  Thomas Carell 5,  Veit Hornung 6
Affiliations

Affiliations

  • 1 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 2 Department of Chemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 3 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 4 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany; Department of Medicine II, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 5 Department of Chemistry, Ludwig-Maximilians-Universität München, Munich, Germany; Center for Integrated Protein Science (CiPSM), Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: thomas.carell@cup.uni-muenchen.de.
  • 6 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany; Center for Integrated Protein Science (CiPSM), Ludwig-Maximilians-Universität München, Munich, Germany; Max Planck Institute of Biochemistry, Martinsried, Germany. Electronic address: hornung@genzentrum.lmu.de.
PMID: 31778653 DOI: 10.1016/j.cell.2019.11.001
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.

Keywords

RNA; RNase T2; TLR8; innate immunity; macrophage; monocyte; pattern recognition; toll-like receptor.

Figures