TLR8 Is a Sensor of RNase T2 Degradation Products.
Amino Acid Motifs
Base Sequence
Cell Line
Endoribonucleases
/ deficiency
Humans
Models, Molecular
Monocytes
/ metabolism
Myeloid Cells
/ metabolism
Nitrogen Isotopes
Oligonucleotides
/ metabolism
Proteolysis
Purines
/ metabolism
RNA
/ metabolism
Staphylococcus aureus
/ metabolism
Toll-Like Receptor 7
/ metabolism
Toll-Like Receptor 8
/ agonists
Uridine
/ metabolism
RNA
RNase T2
TLR8
innate immunity
macrophage
monocyte
pattern recognition
toll-like receptor
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
27 11 2019
27 11 2019
Historique:
received:
10
06
2019
revised:
14
10
2019
accepted:
30
10
2019
entrez:
29
11
2019
pubmed:
30
11
2019
medline:
28
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31778653
pii: S0092-8674(19)31222-X
doi: 10.1016/j.cell.2019.11.001
pmc: PMC7116005
mid: EMS86706
pii:
doi:
Substances chimiques
Nitrogen Isotopes
0
Nitrogen-15
0
Oligonucleotides
0
Purines
0
Toll-Like Receptor 7
0
Toll-Like Receptor 8
0
RNA
63231-63-0
Endoribonucleases
EC 3.1.-
ribonuclease T(2)
EC 3.1.27.1
Uridine
WHI7HQ7H85
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1264-1275.e13Subventions
Organisme : European Research Council
ID : 647858
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
Pays : International
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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